Received: 1 December 2022 Revised: 5 March 2023 Accepted: 23 March 2023

DOI: 10.1002/mco2.265

REVIEW

Understanding and targeting resistance mechanisms in

cancer

Zi-Ning Lei1,2 Qin Tian1 Qiu-Xu Teng2 John N. D. Wurpel2 Leli Zeng1,∗
Yihang Pan1,∗ Zhe-Sheng Chen2,∗

1 Precision,
Medicine Center, Scientific
Research Center, The Seventh Affiliated Abstract
Hospital, Sun Yat-Sen University, Resistance to cancer therapies has been a commonly observed phenomenon in
Shenzhen, P. R. China
clinical practice, which is one of the major causes of treatment failure and poor
2 Department of Pharmaceutical Sciences,
College of Pharmacy and Health Sciences,
patient survival. The reduced responsiveness of cancer cells is a multifaceted
St. John’s University, Queens, New York, phenomenon that can arise from genetic, epigenetic, and microenvironmen-
USA tal factors. Various mechanisms have been discovered and extensively studied,
∗ Correspondence including drug inactivation, reduced intracellular drug accumulation by reduced
Leli Zeng and Yihang Pan, Precision uptake or increased efflux, drug target alteration, activation of compensatory
Medicine Center, Scientific Research
pathways for cell survival, regulation of DNA repair and cell death, tumor plas-
Center, The Seventh Affiliated Hospital,
Sun Yat-Sen University, Shenzhen 518107, ticity, and the regulation from tumor microenvironments (TMEs). To overcome
P. R. China. cancer resistance, a variety of strategies have been proposed, which are designed
Email: zenglli6@mail.sysu.edu.cn and
to enhance the effectiveness of cancer treatment or reduce drug resistance. These
panyih@mail.sysu.edu.cn
include identifying biomarkers that can predict drug response and resistance,
Zhe-Sheng Chen, Department of
Pharmaceutical Sciences, College of identifying new targets, developing new targeted drugs, combination therapies
Pharmacy and Health Sciences, St. John’s targeting multiple signaling pathways, and modulating the TME. The present
University, Queens, NY 11439, USA.
article focuses on the different mechanisms of drug resistance in cancer and the
Email: chenz@stjohns.edu
corresponding tackling approaches with recent updates. Perspectives on poly-
Funding information therapy targeting multiple resistance mechanisms, novel nanoparticle delivery
National Key Research and Development
Program of China, Grant/Award Number:
systems, and advanced drug design tools for overcoming resistance are also
2018YFA0902801; 100 Top Talents reviewed.
Program of Sun Yat-sen University,
Grant/Award Number: ZSQYBRJH0001; KEYWORDS
Guangdong Basic and Applied Basic cancer therapy, combination therapy, drug resistance, resensitization
Research Foundation, Grant/Award
Number: 2021A1515010117; National
Natural Science Foundation of China,
Grant/Award Number: 32270815

1 INTRODUCTION 70 years in more than 60% of the countries worldwide.1

In 2020, there were an estimated 19.3 million newly
Cancer remains a global health burden, ranking first or diagnosed cases and 10 million cancer deaths globally.2
second in the leading causes of death before the age of Currently, the major therapies for cancer include surgery,

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the
original work is properly cited.
© 2023 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.

MedComm. 2023;4:e265. wileyonlinelibrary.com/journal/mco2 1 of 38

https://doi.org/10.1002/mco2.265
2 of 38 LEI et al.

radiation therapy, chemotherapy, hormone therapy, tar- approaches to improve anticancer efficacy via targeting
geted therapy, and immunotherapy, either as monotherapy specific mechanisms, and the progress in developing poly-
or in combination.3–6 Despite the great development and therapy fighting against multiple resistance mechanisms.
improvement of cancer treatment in recent decades,
resistance to cancer therapies has been a commonly
observed phenomenon in clinical practice.7,8 Moreover, 2 RESISTANCE MECHANISMS IN
cancer cells with resistant characteristics often exhibited CANCER AND COMBATING STRATEGIES
cross-resistance to a variety of anticancer drugs that can be
structurally irrelevant, namely, the multidrug resistance Drug resistance in cancer can arise from genetic, epige-
(MDR) phenomenon.9 MDR has been a major obstacle netic, and microenvironmental factors. A better under-
impeding therapeutic success and a dominating cause of standing of the molecular mechanisms underlying cancer
cancer relapse and cancer-related death. resistance is necessary to develop effective strategies to
Cancer therapeutic resistance can be categorized into overcome it. In the following context, the identified resis-
intrinsic and acquired resistance based on the timeline of tance mechanisms will be discussed with reviews of recent
resistance occurrence. The intrinsic resistance, also known research updates, followed by the development of cor-
as primary resistance, is mediated by the endogenous responding combating approaches, such as novel drug
factors that are present in tumor cells or tissues before designs, combination therapies with specific targets, tack-
therapeutic applications, which provide cancer cells with ling alternative signaling pathways, and the modulation of
survival advantages and adaptability to primary therapeu- the TME.
tic stress.10–12 However, acquired drug resistance is devel-
oped after receiving cancer treatment, which is generally
mediated by the adaptive alterations against the given ther- 2.1 Metabolism-associated drug
apy in initially sensitive tumors, resulting in compromised inactivation
treatment effectiveness.13–15 The reduced responsiveness
of cancer cells can be associated with various mecha- The activation and deactivation processes of many
nisms, which usually involve the coactions of genetic chemotherapeutic agents are regulated by drug-
factors and nongenetic contributors. Genetic factors in metabolizing enzymes (DMEs).27 Dysregulation of
tumor cells have been considered critical contributors to DMEs and metabolic signaling pathways, which can lead
therapeutic resistance, such as genetic diversity, acquired to the detoxification of drugs or failure in the conversion
mutations of drug targets, amplification of oncogenes in of drugs into active metabolites, is one of the major
compensatory or bypass pathways, and epigenetic modifi- mechanisms for chemoresistance in cancer.28
cations, which can further affect intratumor heterogeneity, Some anticancer drugs require activation by metabolic
tumor cell plasticity, DNA repair, and the susceptibility of enzymes. For example, the biotransformation of irinote-
tumor cells to cell death pathways, leading to multifactor- can into the active metabolite SN-38 is catalyzed by
mediated resistance.16–18 However, resistant cases in the carboxylesterase,29 and the thymidine phosphorylase is
absence of genetic alteration have been extensively recog- responsible for the activating metabolism of 5-fluorouracil
nized in different types of cancers.19 Phenotype changes (5-FU) into fluorodeoxyuridine monophosphate.30 Cytara-
may be independent of genotype alteration in resistance bine (AraC), a nucleoside drug used in patients with acute
mediated by metabolic inactivation of drugs,20,21 reduced myeloid leukemia (AML) and non-Hodgkin’s lymphoma,
intracellular drug concentration by transporters,22–24 drug relies on the phosphorylation catalyzed by deoxycytidine
compartmentation,25 and drug-induced reversible tran- kinase (DCK) to become the cytotoxic form cytarabine
scriptional or posttranslational regulations on adaptive triphosphate,31 and the deficiency of DCK has been con-
pathways. In addition to the factors within the tumor cells, sidered to be associated with AraC resistance in AML.32
the tumor microenvironment (TME) is also considered Wu et al. reported that DCK mutations were found in 4
to be involved in the development of resistance in some of 10 patients with AML relapse after complete remission
cancers26 (Figure 1). and high-dose AraC post-remission treatment.33 In vitro
Notably, the resistance mechanisms are not mutually studies using drug-selected AraC-resistant AML and lym-
exclusive and can act jointly to induce therapeutic irre- phoma cell models indicated that mutation or deficient
sponsiveness in cancer. Therefore, to develop effective expression and function of DCK could be acquired after
strategies to obviate cancer resistance, it is an urgent receiving AraC therapy, resulting in the reduced cellular
need to gain a better understanding of the mechanisms response to AraC and possible cross-resistance to other
collectively. In this review, we will discuss the discover- nucleoside drugs like gemcitabine.33–35 A potential strat-
ies of the diverse mechanisms of cancer resistance, the egy to overcome DCK deficiency-mediated nucleoside
LEI et al. 3 of 38

F I G U R E 1 Cancer resistance mechanisms, including drug inactivation, insufficient intracellular drug concentration, drug target
alterations, compensatory pathways activation, DNA repair enhancement, and tumor plasticity. Source: This figure was created with
Biorender.com.

drug resistance is using nucleoside analog phosphate cancer resistance,44,45 with CYP1B1 being mostly studied,
prodrugs with anticancer efficacy without the demand which is found to be exclusively overexpressed in various
for DCK phosphorylation,36 among which NUC-1031, types of cancers but has relatively low expression in nor-
a gemcitabine phosphoramidate prodrug, has entered mal tissues.46 Intratumoral CYP1B1 overexpression may
clinical trials for the treatment of gemcitabine-resistant contribute to the diminished effectiveness of a diversity of
cancers.37,38 Other reported attempts in preclinical eval- chemotherapeutic drugs, such as paclitaxel and docetaxel,
uations include enhancing DCK activity by etoposide in mitoxantrone, flutamide, and gemcitabine.47–50 However,
combination with AraC for the treatment of AML,39 and whether the resistance against these drugs is contributed
bypassing the drug resistance mechanism associated with by CYP1B1-catalyzed drug inactivation remains contro-
downregulated DCK expression using second-generation versial. McFadyen et al. suggested that docetaxel was
deoxyadenosine analog clofarabine in acute lymphoblastic metabolized by CYP1B1, and the docetaxel resistance in
leukemia cells.40 CYP1B1 overexpressing Chinese hamster ovary cancer
The other aspect of metabolism-associated anticancer cells could be reversed by a CYP1 inhibitor.51,52 However,
drug inactivation is the detoxification of drugs by metab- Martinez et al. later demonstrated that CYP1B1 did not
olizing enzymes. For instance, certain isoforms of alde- directly inactivate docetaxel because the cytotoxicity of
hyde dehydrogenases (ALDH), including ALDH1A1 and docetaxel in MCF-7 breast cancer cells was not affected
ALDH3A1, have been reported to specifically cause resis- by silencing CYP1B1 or adding recombinant CYP1B1.53
tance against chemotherapeutic drugs of nitrogen mus- Although it is possible that CYP1B1 may play different
tard type, such as cyclophosphamide, mafosfamide, and roles in regulating drug resistance in different cancer types,
ifosfamide.27 In contrast, cytochrome P450 (CYP450) the inhibition of CYP1B1 activity has been considered
in phase I metabolism, and glutathione-S-transferase to be a therapeutic target for improving chemotherapy.54
(GST) as well as uridine diphosphoglucuronosyltrans- Although lacking high selectivity, phytochemicals are
ferase (UGT) in phase II conjugating biotransformation, the most common source of CYP1B1 inhibitors, includ-
are involved in the inactivation of a broader spectrum of ing stilbene, flavonoids, coumarins, anthraquinones, and
anticancer drugs.41,42 alkaloids.55–57 By modifying the structures of phytochem-
The CYP450 enzyme superfamily consists of 57 mem- icals, highly potent and selective inhibitors of CYP1B1
bers that are responsible for the phase I oxidation of most have been developed and under preclinical evaluation,
clinically used drugs.43 Of the CYP450 enzymes, CYP1B1, such as TMS ((E)-2,3′,4,5′-tetramethoxystilbene)58 and α-
2C8, 3A4, and 3A5 have been reported to be correlated to naphthoflavone derivatives.59
4 of 38 LEI et al.

GSTs are involved in drug detoxification in phase II tions on combinations with chemotherapeutic drugs are
metabolism and catalyze the glutathione (GSH) conjuga- lacking; thus, whether the inhibitors can reduce drug inac-
tion to drugs.60 Overexpression of GSTs in cancer cells may tivation remains to be determined. On the other hand,
enhance the detoxification of anticancer drugs.61 More- utilizing prodrugs like canfosfamide (TLK286) and brostal-
over, after GSH conjugation, the conjugated drugs may licin, which are activated by GSTs to become cytotoxic,
become substrates of ATP-binding cassette (ABC) trans- has entered clinical evaluations as a practical strategy to
porters, particularly the MDR-associated proteins (MRPs, circumvent the GST-mediated resistance mechanism.82,83
belongs to ABCC subfamily), and got actively pumped out Similar to GSTs, the UGT enzymes are involved in phase
of the cancer cells.62–64 Among the GST superfamily, GST II metabolism, and they catalyze the glucuronidation pro-
alpha 1 (GSTA1), GST Mu 2 (GSTM2), and GST Pi 1 (GSTP1) cess. Among the three subfamilies (UGT1A, 2A, and 2B)
have been found to be associated with cisplatin resistance of the UGTs, UGT1A enzymes, particularly UGT1A1, have
in ovarian, lung, and gastric cancers.65 Notably, the overex- been shown to overexpress in tumor tissues and play a
pression of GSTP1 has been considered a factor impairing role in resistance to anticancer drugs.20 UGT1A1 is physio-
the efficacy of platinum drugs like cisplatin, carboplatin, logically responsible for facilitating bilirubin elimination
and oxaliplatin by promoting the formation of platinum- by catalyzing the glucuronic acid conjugation of biliru-
GSH conjugates.66,67 The I150V polymorphism of GSTP1 bin. Elevated tumoral UGT1A1 levels can increase the
with a phenotype of reduced enzymatic capacity has been glucuronidation of SN-38, the active metabolite of anti-
correlated with better therapeutic outcomes in gastric can- cancer drug irinotecan, resulting in the inactive SN-38
cer patients receiving oxaliplatin-based chemotherapy.68,69 glucuronide and reduced therapeutic efficacy.84 UGT1A
Besides platinum drugs, the sensitivity to doxorubicin enzymes have also been reported to be associated with pri-
and various alkylating agents in cancer may also be mary resistance to some targeted drugs, such as heat shock
affected by the detoxification process mediated by GSTA protein HSP90 inhibitors ganetespib and luminespib85
subclass, GSTP1, and GSTM1 enzymes.70,71 However, addi- and epidermal growth factor receptor (EGFR) inhibitor
tional mechanisms other than GSH conjugation may erlotinib.86 Drug-induced increase of UGT1A expression
be involved in GST-related chemoresistance to doxoru- has been reported in AML patients treated with rib-
bicin and alkylators, such as free radical scavenging and avirin, which resulted in acquired resistance.87 Apart from
apoptosis suppression via the inhibition of the mitogen- substrate drugs, the efficacy of monoclonal antibody anti-
activated protein kinase (MAPK) pathway.72–74 Thus, there cancer drugs may be affected by UGT1As. For instance,
has been an increasing focus on targeting the GSTs UGT1A6 has been found to be correlated with resistance
to overcome chemoresistance. Inhibitors of GSTs have to programmed cell death 1 (PD-1) antibody nivolumab
been shown effective in treating resistant cancer cells. in patients with advanced renal clear-cell cancer.88 As
Ethacrynic acid and analogs are among the earliest inves- UGTs are not known to conjugate proteins like antibodies,
tigated GST inhibitors that exhibited resensitizing effects UGT-mediated resistance to nivolumab may not be related
on tumor cells to alkylating agents via covalent binding to directed drug inactivation, but to other mechanisms,
to GSTs and reducing the enzyme activity.75,76 NBD- such as indirect metabolism regulations by UGTs and
HEX (6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol) is other resistance-correlated signaling regulations involving
another potent inhibitor against GSTP1, GSTM2, and other UGTs.9 Because of their association with hampered drug
GST isoenzymes,77 which has been found beneficial in response, the expression of UGT1As might be a useful
combating cisplatin-resistant osteosarcoma when used in indicator for patient stratifying so as to avoid the appli-
combination with cisplatin.78 Apart from inhibiting GST cation of substrate drugs to patients who are likely to
activity, NBDHEX can also induce the dissociation of have low response due to high UGT1A levels. Meanwhile,
GSTP1 from its complex with c-Jun N-terminal kinase or UGTs can be potential pharmacological targets to over-
tumor necrosis factor receptor-associated factor 2 thereby come drug resistance in cancer. However, the use of UGT
promoting the activation of apoptosis pathways in can- inhibitors has been limited by toxic side effects, and selec-
cer cells.79 However, one of the significant roadblocks that tivity remains the major challenge in developing novel
GST inhibitors encounter in clinical trials is their insuf- inhibitors of UGTs.89,90
ficient specificity, prompting the development of novel Notably, direct detoxification is not the only mechanism
NBDHEX analogs with improved selectivity, among which of DME-associated cancer resistance, other involving fac-
MC3181 was screened out as a specific GSTP1-1 inhibitor tors like drug–drug interactions and signaling molecules
and tested highly efficient in inhibiting vemurafenib- inherent in cancer cells should be taken into considera-
resistant melanoma in vitro and in vivo.80,81 Although tion in developing strategies targeting metabolic enzymes
the GST inhibitors showed promising effects on inducing in cancer. Regulating the expression and activity of
cell apoptosis via inhibiting GST activities, investiga- DMEs through regulatory signaling transductions can be
LEI et al. 5 of 38

beneficial to overcoming cancer resistance not only by typic binding.101 Fang et al. reported that the uptake of
means of retaining drug bioavailability but also in other membrane-coated nanoparticles in human breast cancer
aspects like inhibiting cancer cell proliferation or invasion. MDA-MB-435 cells was increased by 20-fold compared to
naked nanoparticles.102 Many studies have demonstrated
the selectivity and biosafety of cancer cell membrane-
2.2 Reduced drug uptake based biomimetic nanoparticles using in vitro and in
vivo MDR cancer models,103–105 suggesting a novel drug
Drugs can cross the cell membrane through diffusion, delivery strategy to improve therapeutic efficacy for MDR
endocytosis, or transporters, which can be affected by the cancer.
permeability and lipid composition of the plasma mem- Intracellular drug concentrations largely depend on the
brane, and the functions or expression levels of membrane activity of uptake transporters. The main transporters
transporters. Alteration of cell membrane structure can involved in drug uptake are the drug solute carriers (SLCs).
impair drug diffusion across the plasma membrane and The SLC superfamily consists of more than 400 mem-
the endocytosis process. The plasma membranes from bers categorized into 52 families.106 Chemoresistance-
drug-resistant cancer cells have a different lipid composi- relevant SLCs include the organic anion transporting pro-
tion compared to those from the parental drug-sensitive teins (OATPs), organic cation transporters, concentrative
cells: The cholesterol and phospholipid levels are ele- nucleoside transporters, equilibrative nucleoside trans-
vated, and the protein/lipid ratio is increased up to 60% porters, and copper transporters.107,108 Reduced uptake of
in MDR cells compared to sensitive cells.91 Besides, the chemotherapeutic drugs can be caused by either genetic
slight alkalic pH of the cytoplasm in MDR cancer cells variants resulting in truncated uptake transporter proteins
could attenuate the repulsions between the polar groups with reduced or absent function or acquired expres-
from membrane lipids by shielding the negative charges, sion changes in uptake transporters mediated by phar-
thereby increasing lipid packing and membrane rigidity.92 macological selection pressures. Among them, OATPs
Therefore, MDR cells have plasma membranes with a rel- (SLCO family) are mostly studied. In particular, ampli-
atively lower fluidity and reduced permeability leading fied expression of OATP1A2, OATP1B1, and OATP1B3
to decreased drug absorption.92 Chemotherapeutic drugs, has been found in various cancer tissues,109 which is
including vinblastine, doxorubicin, and cisplatin, are vul- considered associated with chemosensitivity because of
nerable to this resistance mechanism.93–95 Additionally, its role in the uptake of several classes of anticancer
using model membranes by molecular dynamic simula- drugs, such as taxanes, platinum-based drugs, camp-
tions, Rivel et al. recently demonstrated that, cancer cell tothecin analogs, methotrexate, and some tyrosine kinase
membranes are common with the loss of lipid asymme- inhibitors (TKIs).110,111 Downregulation of OATP1B3 was
try compared to normal cell membranes, which may be a reported in a patient-derived docetaxel-resistant prostate
contributor to the slower diffusion of cisplatin into cancer tumor xenograft model, where the intratumoral concen-
cells.96 These findings have suggested that lipid composi- trations of docetaxel and cabazitaxel were both lower than
tion assessment may be useful for cancer prognosis, and chemotherapy-naive tumors. In contrast, prostate tumors
modulating cell membranes can be a potential strategy to with OATP1B3 expression exhibited an increased uptake of
ameliorate drug resistance in cancer. both taxanes and higher chemotherapeutic sensitivity.112
It has been shown that treating cancer cells with Overexpression of OATP1B3 in prostate cancer may be
short-chain ceramides can increase cell membrane per- beneficial to chemotherapy but can be detrimental to
meability and fluidity, resulting in an increased uptake hormone therapy because OATP1B3 drives testosterone
of amphiphilic anticancer drugs such as doxorubicin, uptake in cancer cells, leading to the development of resis-
either in free form or encapsulated form with lipid- tance to androgen deprivation therapy (ADT).113 Increased
based nanoparticles.97,98 The other way to modulate the OATP1B3 expression in prostate cancer can be induced by
lipid composition of the cell membrane is by enhanc- ADT, which provides a clue for sequential therapy design:
ing sphingomyelinase activity using an agonist, such Upregulated tumor SLCO expression following ADT could
as daunorubicin, etoposide, and ara-C, thereby decreas- potentially enhance the uptake of chemotherapeutic drugs
ing sphingomyelin levels and increasing ceramide levels, like taxanes and improve treatment response.114 Inter-
leading to increased membrane fluidity.99,100 Moreover, estingly, the genetic variant of OATP transporters may
biomimetic cell membrane-coated nanoparticle delivery confer resistance to TKIs via the uptake activity instead of
systems are gaining increased recognition. Cancer cell enhancing sensitivity.
membrane-based nanoparticles contain surface proteins Haberkorn et al. recently discovered that cancer-type
from cancer cells; therefore, they can reduce side effects OATP1B3 protein, a splice variant of liver-type OATP1B3, is
by specifically targeting cancer cells through homo- localized in the lysosomal membrane of colorectal cancer
6 of 38 LEI et al.

(CRC) cells and contributes to the transport of encorafenib such as taxanes, vinca alkaloids, and anthracyclines. The
and vemurafenib into lysosomes, resulting in decreased spectrum of anticancer drugs ABCG2 confers resistance
drug concentrations in the cytoplasm and reduced drug to largely overlap with that of ABCB1 and ABCCs but
efficacy.115 Therefore, it is necessary to identify the geno- with some specificities; anthracenedione (such as mitox-
type of intratumorally expressed SLCs in the process of antrone) and camptothecins (such as topotecan and SN-38)
confirming their roles in drug resistance. are especially vulnerable to the efflux activity of ABCG2,
Although enhancing drug uptakes by modulating SLC whereas taxanes and vinca alkaloids are not much affected
transporters may improve chemosensitivity, it may not be by ABCG2.120 Certain clinically used kinase inhibitors,
a practical approach in cancer treatment. Due to the ubiq- such as imatinib, nilotinib, dasatinib, palbociclib, and
uitous expression of SLCs in many tissues, modulating some newly developed targeted drugs, such as OTS964 and
the function of SLCs could interfere with the transport ARS-1620, have also been reported as substrates of ABC
activities of nutrients and xenobiotics in normal tissues, transporters.121–124 Moreover, ABCCs generally have high
which can lead to unfavorable side effects and drug–drug affinities to GSH-conjugated or glucuronate-conjugated
interactions. On the other hand, besides the uptake of anti- forms of drugs; therefore, the efflux activity of ABCC trans-
cancer drugs, modulating SLCs may also influence the porters may be regulated by phase II metabolic enzymes.24
nutrient uptake in cancer cells, risking promoting cancer Additionally, for brain tumors and metastatic cancer in the
progression and metastasis. The best strategy to overcome brain, chemosensitivity is also affected by the o expression
the uptake transporter-mediated resistance in cancer may of ABCB1 and ABCG2 transporters at the luminal mem-
be to use drugs or delivery systems that can circumvent brane of endothelial cells of brain microvessels, which
the aberrant transporter, either with improved diffusion are known to impede anticancer drug delivery across the
efficacy or the capability to utilize alternative transporters. blood–brain barrier.125,126
Ongoing efforts have been taken to develop modulators
of ABC transporters in order to overcome this resistance
2.3 Increased drug efflux mechanism. Numerous small molecule compounds have
been developed and tested as inhibitors against ABC
In addition to reduced drug uptake, drug efflux medi- transporters, particularly ABCB1. There have been three
ated by the overexpression of ABC transporters is the generations of ABCB1 inhibitors; however, these inhibitors
major mechanism contributing to insufficient intracel- have failed to enter clinical use as combination therapy
lular drug concentration. In humans, the ABC trans- with substrate anticancer drugs due to different draw-
porter superfamily consists of 49 members categorized backs. The first generation of ABCB1 inhibitors, such as
into 7 subfamilies (ABCA–ABCG) functioning to trans- verapamil, erythromycin, and cyclosporine A, mostly lacks
port various substrates, including lipids, ions, peptides, sufficient therapeutic efficacy, which results in consider-
and xenobiotics.116 The involvement of ABC transporters able side effects by the required high dosages. Although
in MDR was first discovered in 1976 when ABCB1, which the second-generation inhibitors, such as dexverapamil
is also known as P-glycoprotein (P-gp) or multidrug resisi- and valspodar, have exhibited improved potency, they
tance 1 (MDR1) protein, was discovered in mouse MDR cell failed to proceed to clinical application because of their
lines.117 To date, at least 13 ABC transporters have been unwanted interactions with the CYP450 enzymes leading
found to directly mediate chemoresistance via the efflux to unfavorable pharmacokinetic profiles. The third gen-
of anticancer drugs.118 These ABC transporters mainly dis- eration, exampled by tariquidar and zosuquidar, is able
tribute on the plasma membrane and are triggered upon to overcome the selectivity problem; however, the perfor-
binding to substrate drugs, resulting in an ATP hydrolysis– mance in clinical settings turns out to be unsuccessful due
driven conformational change of the transporter and the to interpatient variability.127 In the recent decade, some
extrusion of the substrate drugs.119 Consequently, the repurposing targeted anticancer drugs, such as selonsertib,
overexpression of these transporters has been correlated tepotinib, and poziotinib, have been discovered as dual
with poor chemotherapy response and unfavorable patient inhibitors for ABCB1 and ABCG2.128–130 Inhibitors that
prognosis in many different types of cancers. Most studies can antagonize both ABCB1- and ABCC1-mediated resis-
have focused on the ABC transporters with wide spec- tance have also been reported, exampled by cediranib and
trums of substrates, such as ABCB1, ABCG2 (also known CBT-1 (tetrandrine).131,132 Targeting multiple ABC trans-
as breast cancer resistance protein), and the ABCC sub- porters may be more prospective given that co-expression
family (also known as multidrug resistance-associated of different ABC transporters is common in tumor tissues
proteins, MRPs) with ABCC1 and ABCC10 as represen- and multitargeting drugs may be beneficial to avoid com-
tative members. Many cytotoxic chemotherapeutic drugs pensatory upregulation of another transporter induced by
can be pumped out of cancer cells by ABCB1 and ABCCs, selective inhibition of a single transporter.133
LEI et al. 7 of 38

Silencing the efflux transporters using gene editing tech-

nologies such as siRNA and CRISPR/Cas9 system has been
increasingly investigated as a novel approach to reducing
drug resistance, which can potentially benefit genetic vari-
ants with intrinsic ABC transporter-related resistance.134
However, many studies conducted gene editing in cell
line-based settings before the step of tumor xenograft
model establishment, which is unlikely to represent gene
therapy for patients. Cancer-targeted delivery remains
a major challenge in developing gene therapies against
ABC transporters. Another trending strategy against ABC
transporter-dependent MDR is to target the regulatory
factors of the ABC transporter expression, including tran-
scriptional regulation and epigenetic modifications on the
gene, and posttranslational modifications on the protein.
Inhibiting the cancer-specific regulators of ABC trans-
porters may render an advantage to targeting tumor tissues F I G U R E 2 Alteration of drug target and activation of
compensating pathways. Cancer resistance associated with
selectively and increasing safety to normal tissues.127 Dys-
alterations in the drug target site or modifications in the structure of
regulated noncoding RNAs, including microRNAs
the target. The reactivation of the downstream pathway bypasses
(miRNAs) and long noncoding RNAs (lncRNAs), have
the other unblocked pathway enabling drug resistance. Activation of
been found to be associated with the overexpression of compensatory signaling pathways to resist cell death leading to drug
ABCB1, ABCG2, and ABCCs in chemoresistant cancers.135 resistance. Source: This figure was created with Biorender.com.
The effect on suppressing ABC transporters and reversing
cancer MDR by nanoparticle-delivered ncRNAs mimics
or inhibitors has been verified from in vitro and in vivo 2.4 Alterations of the drug targets and
studies.136,137 Another epigenetic factor-linked overexpres- activation of compensatory pathways
sion of ABC transporters in cancer is the hypomethylation
of the transporter gene promoter, and evidence has shown The leading limitation of targeted cancer therapies is that
that agonists of DNA methyl transferases can induce the cancer cells can be intrinsically irresponsive or acquire
hypermethylation of the ABCG2 promoter resulting in resistance after a period of treatment because of either the
the lower ABCG2 expression and increased intracellular mutation of target molecules (“on-target” mechanism) or
concentration of substrate drugs.138,139 Alternatively, the tumor cells gaining survival advantages from a new mech-
expression of ABC transporters can be modulated by tar- anism independent of the target (“off-target” mechanism),
geting the upstream regulatory pathways. For instance, in such as the activation of downstream signaling pathways
breast cancer cells, inhibiting the overexpressed receptor or compensatory pathways141,142 (Figure 2).
tyrosine kinase-like orphan receptor 1 (ROR1), which The primary approach to overcome “on-target” mech-
is an upstream regulator of ABCB1 transcription via anism is to develop new generations of targeted drugs
MAPK/extracellular signal-regulated kinase (ERK) and against drug-resistant tumors. For instance, the first-
p53 pathways, can reduce ABCB1-mediated drug efflux and second-generation EGFR–TKIs, such as gefitinib,
and resensitize breast cancer cells to doxorubicin.140 erlotinib, and dacomitinib, are less effective in treating
Another recent study showed that suppressing mito- patients with additional EGFR mutation T790M.143 This
chondrial respiration using methylation-controlled J has led to structural modification and the development
protein mimetics can decrease ATP production thereby of the third-generation EGFR–TKIs therapy. Osimertinib
decreasing the energy for ABCB1 and ABCG2 efflux (AZD9291), a third-generation EGFR–TKI, presented a
activity and overcoming chemoresistance in vitro and superior clinical response and outcome in EGFR-mutated
in vivo.23 non-small cell lung cancer (NSCLC). However, the
Indeed, the direct approach to circumvent this resis- rapidly acquired resistance to osimertinib conferred by
tance mechanism is to avoid using substrate drugs EGFR C797S mutation has been observed.144 Besides,
or develop novel anticancer drugs that can bypass some patients who exhibit primary resistance remain
the efflux transporters. This may rely on advanced unresponsive to third-generation and other newly devel-
computer-aided drug designs to modify drug structures oped EGFR–TKIs. Complete remission is rare, and all
of current known and actively reported substrates of ABC patients eventually develop resistance, suggesting that
transporters. both primary and acquired resistance mechanisms reduce
8 of 38 LEI et al.

the efficacy of the drug.145,146 To reverse these types of was sensitive to TAE684, AP26113, and ASP3026, whereas
resistance, more recently, the fourth-generation EGFR 1151T-ins conferred resistance to all next-generation ALK
inhibitors, which can inhibit both T790M and C797S sig- TKIs. Ceritinib, an ATP-competitive, potent, and selective
naling, have been introduced into clinical evaluation.143 next-generation ALK inhibitor, has shown favorable selec-
So far, EAI045 is the first allosteric TKI developed for this tivity to ALK.159 In clinical studies involving ALK-positive
purpose. The C797S mutation is unlikely to impair the NSCLC patients, ceritinib has exhibited marked antitumor
efficacy of EAI045 because its allosteric binding pocket activity has been observed in both crizotinib-relapsed and
is not affected by this cysteine residue. EGFR receptor crizotinib-naive patients.160,161 On the basis of this impres-
dimerization invalidates drug-mediated inhibition alone. sive clinical activity, ceritinib received FDA approval on
The activity against T790M and C797S can be restored April 29, 2014.
by a combination regimen with cetuximab, an antibody Despite increasing successes in efforts to target onco-
against EGFR dimerization.147 Other fourth-generation genic driver amplifications or mutations, several of the
EGFR-TKIs, such as JND3229 and JBJ-04-125-02, were most formidable oncogenes and tumor suppressor genes
recently found to be active in EGFR C797S-T790M-L858R remain undruggable, including RAS (KRAS, NRAS, and
signal transduction in vitro and in vivo.148,149 HRAS) and RAF (ARAF, BRAF, and CRAF). Effective
For the first-generation tropomyosin receptor kinase targeting of KRAS signaling has been tough to realize
(TRK) kinase inhibitors, such as entrectinib and larotrec- in patients.162,163 Blocking the localization of KRAS at
tinib, the secondary mutations occurring at the ATP the plasma membrane, a vital element for its activa-
binding pocket of the TRK kinase domain, includ- tion, has been ineffective because multiple compensatory
ing G667C and G595R mutations in NTRK1 gene, and pathways modulate this process. Similarly, targeting effec-
G696A and G623R mutations in NTRK3 gene, are com- tor signaling downstream of KRAS has not achieved
mon acquired-resistance mechanisms.150,151 In addition, remarkable clinical benefits on the account of paradox-
second-generation TRK inhibitors like selitrectinib have ical signaling activation generated by the inhibitor or
been developed to overcome this acquired resistance. because of on-target toxicity limiting the maximum tol-
The multitargeted TKI crizotinib was approved by erated dose in patients.164,165 Tumor cells with KRAS or
the Food and Drug Administration (FDA) in 2011 to BRAFV600E mutations are addicted to a downstream ERK
treat patients with advanced NSCLC harboring ALK signaling cascade for their growth, viability, and other
rearrangements.152 However, despite a high response rate malignant properties.166 The adaption of selective inhibitor
of 60% in ALK-rearranged NSCLC, most patients develop target KRASG12C only briefly inhibits KRAS within 1–
resistance to crizotinib, typically within 1–2 years. Studies 3 days of treatment, and initial signaling suppression is
of ALK-rearranged lung cancers with acquired resistance accompanied by the re-storage of active KRAS and reac-
to crizotinib have identified ALK fusion gene amplifica- tivation of ERK1/2 signaling pathway.167,168 Accumulation
tion and secondary ALK tyrosine kinase domain mutations of active KRAS illustrates that compensatory activation
in about one third of cases.153,154 To date, seven differ- of upstream receptor tyrosine kinases (RTKs), including
ent acquired resistance mutations have been identified EGFR, is to a large extent responsible for the adaptive
among crizotinib-resistant patients. The most frequently alterations noted during KRASG12C inhibitor treatment.
identified secondary mutations are L1196M and G1269A. In In RASMut tumors, RAF inhibitors (RAFis) are ineffective
addition to these mutations, the 1151T-ins, L1152R, C1156Y, because they drive paradoxical ERK1/2 pathway activation
G1202R, and S1206Y mutations have also been detected and adventitious tumor progression.169 However, MAPK
in crizotinib-resistant cancers.155–157 In approximately one kinase (MEK) inhibitors (MEKis) do not present the same
third of crizotinib-resistant tumors, there is evidence of limitation as RAFis, but the relief of feedback inhibi-
activation of bypass signaling tracts such as EGFR.157 In tion and pathway reactivation restricts MEKi monotherapy
the remaining one third of crizotinib-resistant tumors, in RASMut -driven tumors.166,170 By the amplification of
the resistance mechanisms remain to be identified. Next- KRASG13D or BRAFV600E , CRC cells acquire resistance
generation ALK inhibitors with improved potency and to the MEKi.171 Furthermore, MEKi resistance driven by
selectivity compared with crizotinib have been developed BRAFV600E amplification is thoroughly reversible upon
to overcome crizotinib resistance in the clinic. The abil- prolonged drug withdrawal as BRAFV600E amplification
ity of several ALK TKIs (TAE684, AP26113, ASP3026, and brings about a selective disadvantage in the absence of
CH5424802) to inhibit ALK activity was evaluated in mod- MEKi, and MEKi withdrawal drives ERK1/2 activation
els harboring different ALK secondary mutations.153,158 beyond a key point that is optimal for cell proliferation
These studies revealed variable sensitivity to these ALK and viability.172 Remarkably, MEKi resistance driven by
inhibitors depending on the specific resistance mutation KRASG13D amplification is not reversible. Upon MEKi
present. For example, the gatekeeper L1196M mutation withdrawal, CRC cells experience an ERK1/2-dependent
LEI et al. 9 of 38

epithelial-to-mesenchymal transition (EMT) and emerge NRASQ61K has occurred while entrectinib treatment.187
resistance to frequently used chemotherapeutics instead Upregulated HER2 phosphorylation has been identified in
of exhibiting growth defects.172 Consequently, the appear- patient-derived, crizotinib-resistant CD74–ROS1-positive
ance of MEKi resistance, drug-addiction, and the possible CUTO23 (NSCLC cell line), and afatinib combined applied
options of intermittent dosing schedules, may depend on recovered crizotinib sensitivity in CUTO23.188 Usually,
the nature of the amplified oncogenes (e.g., KRASG13D ROS1 fusions de novo barely co-occur with EGFR muta-
BRAFV600E ), further highlighting the hardships of target- tions in clinic,189 but ROS1 fusions come into sight as resis-
ing RAS and RAF mutant tumors. Mutations of tumor tance mechanisms to EGFR–TKI therapy in EGFR-mutant
suppressor can also result in resistance to targeted ther- NSCLC,190 suggesting feedback or potential signaling reci-
apies, for example, mutations in phosphatase and tensin procity among ROS1 and EGFR. In patients treated with
homolog deleted on chromosome 10 (PTEN) can acti- ROS1–TKIs, activating PIK3CA mutations have also been
vate phosphatidylinositol-3-kinase (PI3K) β signaling in reported.188,191 In ROS1 fusion-positive NSCLCs patients
response to PI3Kα inhibitors,173 as well as reverse muta- treated with ROS1–TKIs, 11% were found to have con-
tions in breast cancer 1 (BRCA1) or BRCA2 in response to current MEK/MAPK alterations.192 Subsequently, it was
poly(ADP-ribose) polymerase (PARP) inhibitors.174 proved that the deletion of MEK1 or MEKK1 in cells
In NSCLC, the majority of all EGFR mutations are conferred resistance to ROS1–TKIs and combined ROS1
EGFRL858R in exon 21 and activating EGFR exon 19 dele- and MEKis inhibited cell growth.192 Until 2020, MET
tions, and tumor cells harboring the specific activating amplification was found to act as an important partic-
mutations exhibit high sensitivity to EGFR–TKIs.175,176 ipator of ROS1–TKI (e.g., lorlatinib) resistance.141 ROS1
These constitutively activate mutant EGFR oncoproteins kinase domain mutations that trigger the resistance of
signaling by regulating MAPK and PI3K/AKT/mTOR sig- ROS1 fusion-positive tumors to ROS1–TKIs have been
naling cascades to promote tumorigenesis.177 In a series identified by various preclinical and clinical studies.188
of EGFR–TKI-resistant tumor samples, 1% of patients Some of these mutations are paralogous to ALK resis-
exhibited resistance to early-generation EGFR–TKIs via tance mutations that emerge with targeted therapy for
the acquisition of BRAFV600E or BRAFG469A .178 Increased ALK fusions,193 among which ROS1G2032R is the most com-
mTOR level was related to EGFR–TKI resistance in clin- mon resistance substitution observed in patients treated
ical samples,179 and in mouse models, the application with crizotinib.194 Considering its clinical benefits but its
of rapamycin (mTOR inhibitor) presented the positive lack of activity against ROS1G2032R , lorlatinib can rebuild
progression of EGFRmut lung tumors.180 EGFR–TKIs in enduring disease control in ROS1-rearranged tumors with
combination with PI3K/AKT/mTOR signaling pathway the limited spectrum of resistance mutations.195 However,
inhibitors have proved improved tolerability and efficacy. FDA has conferred repotrectinib as the Fast Track Des-
Another pattern of acquired resistance to kinase inhibi- ignation agent in patients who previously experienced
tion is the amplification of upstream genes, which can one ROS1–TKI and platinum-doublet chemotherapy. Up to
exemplify by mesenchymal–epithelial transition (MET) now, next-generation ROS1–TKIs have not been approved
amplification leading to resistance to EGFR–TKIs.181 for the treatment of ROS1 rearrangement-positive tumors.
The clinical value of proto-oncogene 1 (ROS1)-directed
TKIs was first prospectively explored in NSCLC patients,
and in 2016, the FDA and EMA approved crizotinib for the 2.5 Enhanced DNA repair
treatment of advanced-stage ROS1-rearranged NSCLC.182
Afterward, new ROS1–TKIs got into clinical trial, leading The DNA damage response (DDR) is a mechanism for
to the FDA and Ministry of Health, Labor and Wel- repairing drug-induced DNA damage. Mutation or dys-
fare of Japan approvals of entrectinib for the treatment regulation of certain genes and DDR mechanisms are
of ROS1-aberrant NSCLC. So far, all developed ROS1– common in many types of cancer and can influence the
TKIs are multikinase inhibitors, which can also target sensitivity to DNA-damaging chemotherapy drugs, such
MET (e.g., crizotinib and cabozantinib), ALK (e.g., ceri- as cisplatin and 5-FU.196,197 The nucleotide excision repair
tinib and crizotinib), TRK (e.g., entrectinib and repotrec- (NER) responsible for repairing DNA damage repairing
tinib), and several other kinases (e.g., SRC, EGFR, JAK2, and mismatch repair (MMR) responsible for maintaining
and FLT3) with equivalent or lower potency.183–185 Var- genomic integrity are known to be related to 5-FU resis-
ious compensatory pathways involved in TKI therapy tance. It is demonstrated by Liu et al. that the acquired
of ROS1-rearranged tumors progression, such as KRAS, upregulation of the excision repair cross-complementing
NRAS, BRAF, HER2, EGFR, MEK, and MET. For exam- 1 (ERCC1), a component of the NER system, was induced
ple, mutations of KRASG12D and BRAFV600E have emerged by 5-FU treatment in gastric cancer cells, which can sub-
with crizotinib treatment in the clinical testing,186 and sequently weaken the anticancer activity of 5-FU. Further
10 of 38 LEI et al.

mechanism studies revealed that 5-FU-induced ERCC1 glioblastoma (GBM) patients to methylating chemother-
overexpression may be regulated by ERK 1/2 and p38 apeutic agents like temozolomide.206 In breast cancer,
signaling-mediated activation of the transcription factor c- the hypermethylation of the BRCA1 promoter has been
jun/activator protein-1, which provides a clue to overcome associated with decreased BRCA1 expression and sensi-
this resistance mechanism using ERK inhibitors or p38 tivity to DNA-damaging drugs and PARP inhibitors.207
kinase inhibitors.198 In contrast, the role of MMR in 5-FU In contrast, the hypermethylation of the MLH1 promoter
resistance remains uncertain. It was recently reported by has been associated with decreased MLH1 expression and
Oliver et al. that both MMR-proficient and MMR-deficient DNA repair capacity in cancer cells, which can increase
CRC cells exhibited 5-FU resistance after a period of treat- the accumulation of somatic mutation in cancer cells and
ment, suggesting that 5-FU chemoresistance in CRC cells induce drug resistance.208 These findings highlight the
may be independent of MMR status. Nevertheless, MMR complex interplay among DNA methylation, DNA repair,
genes human homolog 1 (hMLH1), a component of MMR, and cancer resistance and suggest that targeting DNA
was upregulated in an MMR-deficient cell line, which methylation may be a promising strategy for overcoming
indicated a potential involvement in 5-FU sensitivity.199 drug resistance in cancer.
MMR deficient–associated microsatellite instability has Histone modifications also play an important role in
been linked to cisplatin resistance in clinical germ cell DNA repair and cancer resistance. A recent study demon-
tumor sample,200 whereas in ovarian cancer, cisplatin strated that, in high-grade serous ovarian carcinoma cell
resistance is generally related to homologous recom- lines and patient-derived xenograft models, the upregu-
bination repair (HRR) for DNA damage. The BRCA1 lation of histone methyltransferases EHMT1 and EHMT2
and BRCA2 tumor suppressor genes are critical for the are responsible for the trimethylation of histone H3 lysine
HRR of DNA double-strand breaks by the HRR pathway; 9 (H3K9me3) and contribute to PARP inhibitor resistance
therefore, BRCA1/BRCA2-mutated ovarian cancers are through inhibiting the expression of the tumor suppressor
usually more sensitive to cisplatin.201 However, acquired gene CDKN1A, which is involved in the regulation of the
secondary mutations of BRCA1/2 induced by long- cell cycle and DNA repair.209 However, another study
term cisplatin exposure can reconstruct the function of showed that the loss of the histone methyltransferase,
BRCA1/2 and enhance DNA repair, resulting in resistance enhancer of zeste homolog 2 (EZH2), led to decrease in
to cisplatin200 as well as inhibitors of DNA repair poly global H3K27 methylation, resulting in the upregulation
(ADP-ribose) polymerase (PARP).202 Recently, another of genes associated with cisplatin resistance and the
DNA repair–related protein, actin-like protein ACTL6A, downregulation of genes involved in DDR. This study
has been reported to promote DNA lesion induced by also showed that treatment with EZH2 inhibitors could
cisplatin damage through the SWI/SNF chromatin remod- reverse chemotherapy resistance in TGCTs, indicating the
eling complex in several types of cancers, suggesting a potential for epigenetic therapies in treating drug-resistant
novel cisplatin-resistance mechanism. As ACTL6A is also tumors.210
a component of NuA4/TIP60 histone acetylase, treatment MiRNAs and LncRNAs have been implicated in the reg-
with a histone deacetylase inhibitor can be useful to atten- ulation of multiple pathways, including DNA repair. For
uate this resistance mechanism and resensitize tumor example, miR-15a and miR-16 are found to downregulate
cells to cisplatin.203 the expression of B-lymphoma Moloney murine leukemia
In addition to gene mutations that activate DNA repair virus insertion region-1 protein (BMI1), a protein involved
genes, epigenetic regulations, including DNA methyla- in the ubiquitin-mediated DNA repair pathway, thereby
tion, histone modifications, and miRNAs, can all affect decreasing DNA repair capacity and increased sensitivity
the expression of DNA repair genes, contributing to drug of breast cancer cells to doxorubicin treatment.211 Upreg-
resistance. ulation of LncRNA HOTAIR has been observed in breast
DNA methylation can suppress gene expression. In the cancer cells following radiation therapy, which promotes
context of DNA repair–associated drug resistance, DNA DNA repair and radioresistance by interacting with the
methylation has been implicated in the regulation of EZH2 protein.212 These findings have implicated that the
key DNA repair genes, such as O6 -methylguanine-DNA specific miRNAs and LncRNAs could serve as biomarkers
methyltransferase (MGMT), BRCA1/2, and MLH1. MGMT for predicting therapeutic response in cancer patients and
promoter methylation is associated with a loss of MGMT could be potential target to overcome drug resistance.
protein expression and activity in the tumor and has
been shown to correlate with a better outcome of ther- 2.6 Inhibition of cell death
apy in several studies.204,205 Consequently, the methylation
status of the MGMT promoter has emerged as a use- Cancerous cells are known to highly regulate the apoptotic
ful biomarker for predicting the treatment response of pathways, and apoptosis plays different roles in tumor:
LEI et al. 11 of 38

eliminates infected cells from the human body, assists and respond to stress through recycling damaged cellu-
the functioning of the immune system, as well as con- lar organelles, proteins, and other cellular components.223
tributes to the maintenance of homeostasis.213 Generally, In tumors, autophagy is a double-edged sword, and its
those signals induce the activation of effector caspases anti- or pro-tumorigenic character relies on the onco-
that mediate intracellular signaling, resulting in DNA frag- genic context and stage of tumorigenesis.224 In the early
mentation. Caspase mutations occurring in tumor therapy stages of tumorigenesis, autophagy exhibits tumor sup-
chemoresistance have been widely reported. For exam- pression function by removing aggregated and misfolded
ple, caspase-8 mutations are mainly detected in gastric proteins, damaged organelles, limiting cell growth, necro-
cancers, and the procaspase-8Q482H mutation abrogates sis, and chronic inflammation.225 Upon advanced periods
apoptosis by leading to the dimerization attenuation of of tumor progression, autophagy helps to keep tumor
the procaspase-8 protein monomers, resulting in resis- cell survival and increases cellular resistance by con-
tance to chemotherapy.214 The intrinsic apoptosis pathway ferring stress tolerance by providing the recycling sub-
by mitochondrial damage is activated through numer- strate to promote cancer cell survival and contributes to
ous exogenous or endogenous stimuli that induce DNA cancer progression and drug resistance.226 For example,
damage.215 The activation of this pathway involves the acti- in ovarian cancer,227 leukemia,228 hepatocellular carci-
vation or inhibition of proteins from the B-cell lymphoma noma (HCC),229 and CRC,230 the increased levels of basal
2 (Bcl-2) family, and multiple drugs are known to induce autophagy contribute to tumor cell growth and increase
apoptosis of cancerous cells through this mechanism. For aggressiveness. Another study showed that autophagy was
example, small molecule RAF kinase inhibitor sorafenib activated in mice with Myc-induced lymphomas when
induces apoptosis of AML through the downregulation of treated by chemotherapy; autophagy inhibition sensitizes
Mcl-1 (an anti-apoptotic protein) and the upregulation of tumor cells to cell death induced by chemotherapeutic
BIM (an activator of the intrinsic pathway).216 Previous agents, suggesting that autophagy induction leads to a self-
studies (in vitro and in vivo) have suggested that upregu- defense effect in this case.231 Several barriers result from
lating of Bcl-2 in breast cancer cells promotes metastasis TKI resistances that emerge in a later period of tumor
to the lung in mice by the EMT process and triggers resis- attribute to the mutation in the kinase domain or function
tance to chemotherapy (PD168393, a specific inhibitor of of basal autophagy as housekeeping as well as the regula-
EGFR; AG490, an inhibitor of JAK2).217,218 In the treatment tor of RTK activity, which challenges effective treatment
of hematological malignancies, the aim to integrate the against cancer targeted therapy. Therefore, the combina-
application of Bcl-2 inhibitors has led to further research tion of autophagy modulators with TKIs has been consid-
and development of Bcl-2 selective and dual Bcl-2 and ered in cancer therapy. For example, in NSCLC, erlotinib
Bcl-xL inhibitors. Similar to ABT-199 (the first-ever Bcl-2 and gefitinib can induce a high level of autophagy as a
inhibitor known as Venetoclax), Navitoclax (ABT-263) is drug resistance and cytoprotective mechanism that was
one of the most studied dual inhibitors; it acts as a BH3- accompanied by the suppression of the PI3K/AKT/mTOR
mimetic, permitting the release of BH3-only proteins and signaling cascade. In addition, autophagy inhibition by
further MOMP by Bax/Bak activation.219 One clinical trial the pharmacological inhibitor, chloroquine, and siRNAs
detected the effect of ABT-263 in 118 chronic lymphocytic targeting autophagy-related gene 5 (ATG5) and ATG7,
leukemia (CLL) patients and reported partial responses in enhances the erlotinib and gefitinib cytotoxicity.232 Gas-
34.6% of patients in phase I trials.220 Rituximab, a mono- trointestinal stromal tumors (GISTs), in which the acti-
clonal antibody targeting the protein CD-20 was combined vation of CD117, stem cell growth factor receptor, or
with ABT-263 and showed a statistically significant over- platelet-derived growth factor receptor-α mutations comes
all response rate of 70% in untreated patients with CLL up, rarely answer to only-imatinib mesylate (IM) treat-
compared to rituximab alone.221 However, because of the ment. IM triggers autophagy as a survival mechanism in
character of Bcl-xL in platelet survival, a main concern quiescent GIST cells that result in acquired resistance and
with ABT-263 is the negative effect: inducing thrombo- ineffective treatment. Nevertheless, the combination ther-
cytopenia in a dose-dependent manner. Furthermore, the apy by which IM was used with siRNAs targeting ATGs
additional concern is regarding the emergence of tumor potentiates GIST cytotoxicity.233 Another study revealed
cell resistance to this agent, through the upregulation that IM induces autophagy in chronic myeloid leukemia
of Mcl-1 phosphorylation and further sequestration of by induction of ER stress in a different way from apopto-
the proapoptotic protein Bim.222 Overall, the clinical use sis induction and the combination therapy with autophagy
of ABT-263 is under restriction, and further studies are inhibition using either siRNA targeting ATGs or pharma-
necessary before its approval. cological inhibitors promotes cell death. Moreover, other
Autophagy is a conserved and tightly regulated catabolic TKIs like dasatinib or nilotinib, combined with autophagy
self-degrading mechanism whereby cells keep homeostasis suppression treatment, exhibited similar effects.234
12 of 38 LEI et al.

Ferroptosis is an intracellular iron-dependent mecha- cancer, the activation of ACSL4 conquered gemcitabine
nism of cell death that is distinct from apoptosis, necrosis, resistance by inducing ferroptosis.247
and autophagy.235 Extensive preclinical and clinical stud- Recently, Tsvetkov et al. revealed a previously unchar-
ies have concentrated on conquering drug resistance, acterized cell death mechanism termed cuproptosis.248
and inducing ferroptosis has been proven to reverse Cuproptosis a mechanism distinct from all other known
drug resistance. According to the theoretical framework manners of regulated cell death, such as apoptosis, pyrop-
for initiating the process of ferroptosis, there are three tosis, necroptosis, and ferroptosis. Cuproptosis is regulated
diverse pathways to reverse chemotherapy resistance: by protein lipoylation in the citric acid (TCA) cycle, where
the canonical glutathione peroxidase 4 (GPX4)-regulated lipoylation is necessary for enzymatic function.249,250 Their
pathway, iron metabolism pathway, and lipid metabolism research illuminates the connection between the sensi-
pathway.236 Genetic inhibition of GPX4 can induce tumor tivity to copper-mediated cell death and mitochondrial
cell ferroptosis and suppress tumor growth in vivo.237 In metabolism: respiring. TCA-cycle active cells have upreg-
addition, the inactivation of GPX4 results in the accumu- ulated levels of lipoylated TCA enzymes (particularly, the
lation of phospholipid hydroperoxides to induce cell mem- pyruvate dehydrogenase complex), and the lipoyl moiety
brane damage and ferroptotic death.238 In GBM, androgen acts as a direct copper binder, inducing the aggregation
receptor ubiquitination induced by the curcumin analog of lipoylated proteins and destabilization of Fe–S clus-
was found to inhibit GPX4, generating ferroptosis and ter proteins, ultimately leading to proteotoxic stress and
reversing temozolomide resistance.239 In CRC, elevated cell death.248 Genetic variation in copper homeostasis
kinesin family member 20A (KIF20A) expression was leads to serious disease, and copper chelators and copper
associated with oxaliplatin resistance, cellular ferroptosis ionophores have been proposed as anticancer agents.251–254
may be induced by disturbing the KIF20A/NUAK1/GPX4 For genetic disorders of copper homeostasis like Menke’s
signaling pathway to reverse the resistance of CRC to disease and Wilson’s disease, copper chelation is an effec-
oxaliplatin.240 Cystine/glutamate antiporter (xCT) sys- tive treatment.255 However, in tumors, copper ionophores
tem, as an essential component of the GPX4-regulated like elesclomol have been tested in clinical trials, but nei-
pathway, has also been revealed to be capable of trig- ther the benefit of a biomarker of the appropriate patient
gering ferroptosis. A study reported that erastin and population nor an understanding of the drug’s mechanism
sulfasalazine (xCT system inhibitors) could induce head- of action is considered in such testing. For example, a phase
and-neck cancer cell ferroptosis and overcome cisplatin III combination clinical trial of elesclomol in melanoma
resistance.241 Another study showed that in gastric can- patients indicated the absence of efficacy in this unse-
cer, inducing ferroptosis by restraining Nrf2/Keap1/xCT lected population, yet a post hoc analysis of samples with
signaling, can sensitize cisplatin-resistant cells to cisplatin low plasma lactate dehydrogenase (LDH) levels displayed
treatment.242 Ferroptosis is defined as an iron-catalyzed evidence of antitumor activity.256 Low LDH represents a
form of regulated necrosis.243 Upregulation of cellular higher cellular dependency on mitochondrial metabolism,
labile iron pool (LIP) leads to increase vulnerability to in accordance with Tsvetkov’s finding that cells more
ferroptosis. Du et al. reported that tumor cell ferropto- reliant on mitochondrial respiration are nearly 1000-fold
sis contributed to catastrophic LIP accumulation after more sensitive to copper ionophores than cells going
dihydroartemisinin treatment in pancreatic ductal ade- through glycolysis. Considering the distinct mechanism of
nocarcinoma, and dihydroartemisinin treatment could cuproptosis from other forms of cell death, deeply under-
overcome cisplatin resistance by triggering ferroptosis.243 standing how cuproptosis is initiated, progressed, and
Divalent metal transporter 1 (DMT1) and secreted gly- ultimately executed may exhibit great significance for spe-
coprotein lipocalin-2 are both key proteins in regulating cific therapeutic interventions and workable combination
iron homeostasis. Turcu et al. found that elevated cellu- therapies.257
lar LIP caused by DMT1 inhibition induced ferroptosis,
thereby wiping out breast cancer stem cells (CSCs) and
reversing MDR.244 A recent report by Chaudhary et al. 2.7 Regulation from tumor
indicated that targeting lipocalin-2 overcame 5-FU resis- microenvironment
tance in CRC by elevating intracellular iron levels, which
in turn resulted in tumor cell ferroptosis.245 The lipid How tumor cells react to therapy not merely relies on
metabolism pathway is also tightly associated with cell vul- the genomic aberrations they harbor but also is medi-
nerability to ferroptosis. Acyl–CoA synthetase long-chain ated by the TME.258 TME is a complicated element of
family member 4 (ACSL4), an important participant in fer- tumors and is quite heterogeneous.259 The significant
roptosis execution, is involved in producing phospholipid character of the TME in changing tumor activity has been
hydroperoxides in an enzymatic manner.246 In pancreatic stated by plentiful studies uncovering how the TME can
LEI et al. 13 of 38

F I G U R E 3 Adaptive mechanisms of cancer cell survival and cancer resistance driven by tumor microenvironment (TME). The TME is
important for cancer resistance; the cancer cells within the TME can undergo a series of adaptive changes, such as various cellular
components can complement the growth signal of cancer cells, combining with angiogenesis to promote cell survival and resistance. The
immunosuppression caused by the TME prevents immune cells from killing cancer cells. The induction of the TGF-β signaling and the
release of prostaglandin E2 (PGE2) resulting in further augmentation of self-renewal and plasticity of cancer stem cells (CSCs). Source: This
figure was created with Biorender.com.

influence the malignant behavior and therapeutic resis- and elevates sensitivity to HER2-targeting agents of breast
tance of the tumor cells260 (Figure 3). The TME contains cancer cells.265,266 In melanoma, CAFs promote cell
a multitudinous cellular and acellular milieu; diverse metastasis and drug resistance by upregulating the level
stromal and immune cells are recruited to develop and of matrix metalloproteinase 1 (MMP1) and MMP2.267 As a
maintain such self-sustained circumstances.261 The extra- significant aspect of the TME, the cell-to-ECM interaction
cellular matrix (ECM), including proteins like laminins, and cellular crosstalk induce the release of soluble factors
fibronectin, proteoglycans, vitronectin, tenascin-C, and (like, angiogenic factors and chemokines) in charge of
collagen, devotes to the majority component of the ECM remodeling and immune evasion, which further
TME and is vital for the maintenance of TME and the bring about therapy resistance. For example, the interac-
induction of cellular adhesion, migration, invasion, and tion between α4β1 integrin on cancer cells and fibronectin
metastasis.262 Moreover, the composition and organiza- induce drug resistance in AML and CLL through the
tion of ECM can also influence the sensitivity to drug PI3K/AKT/BCL2 signaling pathway.268,269 Stromal cell–
therapy. For example, it has been reported that ECM derived factor 1 (SDF1) can interplay with CXC motif
proteins (laminin, fibronectin, and vitronectin) medi- chemokine receptor type 4 (CXCR4) and activate AKT
ated cell adhesion-mediated drug resistance (cilengitide, and ERK1/2 signaling pathways, resulting in antiapoptotic
an integrin inhibitor, and/or carmustine, an alkylating effects and contributing to tumor cell survival in CLL
chemotherapy) in glioblastoma (GBM). Enrichment cells.270 In AML cells, CXCR4 activation induced by
of the above proteins in the TME facilitates GBM cell SDF1-mediated leads to resistance to cytarabine through
proliferation via integrin αv -mediated FAK/paxillin/AKT reducing miRNA let-7a and facilitating transcriptional
signaling cascade and suppresses p53-involved tumor activation of MYC and Bcl-xl.271 In CRC, CXCR4 is upreg-
apoptosis.263 In breast cancer, cancer-associated fibrob- ulated in chemoresistant tumor cells, and lymph node–
lasts (CAFs) promote drug resistance by increasing derived stromal cells enhance resistance to oxaliplatin and
hyaluronan production.264 Another study showed that 5-FU via an SDF1/CXCR4 dependent manner.272
the inhibition of the β1 integrin activity by monoclonal Exosomes, intraluminal vesicles of multivesicular bod-
antibody AIIB2 markedly promotes radiotherapy efficacy ies with a diameter of 30–100 nm, are ubiquitously present
14 of 38 LEI et al.

in most body fluids like blood, cerebrospinal fluids, urine, apoptosis regulator Bcl-2/BAX signaling.292 In NSCLC,
saliva, and lymphatic fluid.273,274 Exosome contents not exosome-mediated miR-21 delivery induces the upreg-
only reflect the composition of the donor cell but also mir- ulation of p-AKT level, thereby resulting in increased
ror a regulated sorting mechanism.275 A complicated of gefitinib resistance.293 Exosomes containing miR-32-5p
multifarious proteins, including ECM proteins, enzymes, generate MDR in HCC cells by inhibiting PTEN, activating
transcription factors, receptors, lipids, and nucleic acids PI3K/AKT signaling cascade and promoting angiogenesis
(DNA, mRNA, and miRNA) inside and on the surface and EMT process.294 HCC-derived exosomes containing
of the exosomes constitute their content.276,277 Exten- miR-221 induce sorafenib resistance through modulating
sive evidence has shown that exosome-mediated factors apoptosis inhibition and caspase-3 activity.295 Consider-
can promote tumorigenesis, metastasis, and therapeutic ing that exosomes are involved in various pathophysi-
resistance of cancer cells via intercellular communication ological conditions, understanding the molecular mech-
within TME.273,278,279 Tumor-derived exosomes (TDEs) anisms underlying exosome biogenesis and chemoresis-
involve in the initiation, development, and progression tance will benefit in developing novel therapeutics tar-
of diverse tumor courses, including angiogenesis, TME geting exosome-mediated tumorigenesis, progression, and
remodeling, metastasis, and therapy resistance.273,279,280 chemoresistance.
TDEs induce the differentiation of various kinds of One of the important functions of TDEs is to induce
TME cells to CAFs that are the main cell popula- tumor vascular development. Angiogenesis, a multistep
tion of TME in the majority of tumors; thus, exo- course by which cancers form new vasculature, is essential
somes play a vital role in ECM remodeling and TME for tumor progression.296 Since Judah Folkman revealed
reprogramming.281,282 Exosomes derived from CAFs con- the significant character of vascular networks for the
tain different molecules such as miRNAs and growth proliferation and progression of solid tumors, establishing
factors that have distinct influences on the target cells angiogenesis as a therapeutic target has become a focal
of TME. For example, the gemcitabine therapy of CAFs aim.297 Up to now, antiangiogenic therapy has emerged
in pancreatic cancer stimulates the expression of miR- as significant targeted therapeutic and diverse antian-
146a and snail and prolonged exosome secretion, thereby giogenic agents are currently used in combination with
promoting epithelial cell proliferation.283 Drug-resistant other chemotherapeutic drugs for the treatment of various
tumor cells can pack the chemotherapeutic drugs in malignant tumors. Nowadays, over 11 antiangiogenic
exosomes and shuttle therapeutic agents out of cancer drugs have been approved by the U.S. FDA, including
cells.283 Besides, the delivery of exosomal cargo contain- bevacizumab, aflibercept, sorafenib, ramucirumab, suni-
ing proteins, mRNA, and miRNA to cancerous cells is tinib, pazopanib, axitinib, vandetanib, Lenvatinib, and
related to therapeutic resistance.284,285 For instance, GBM regorafenib.298 However, the treatment is in doubt on
cell–derived exosomes, which comprise MET-protein and the grounds of sustainable efficacy, side effects, off-target
tyrosine phosphatase receptor type Z (PTPRZ1) fusion pro- toxicities, and therapy resistance.299,300 Clinical and
teins, obtain temozolomide resistance via EMT.286 TDEs experimental studies have illustrated that cancers employ
from gemcitabine-resistant pancreatic cancer cells induce compensatory/alternative/bypass angiogenic pathways
chemoresistance by trapping MRP5 and P-gp or letting and other adaptive mechanisms for their sustained
gemcitabine to flow back to TME.287 Exosomes derived growth, proliferation, and metastasis, after undergoing
from MCF7WT breast cancer cells contain P-gp and ubiq- a therapy episode(s) with antiangiogenic drugs. That is,
uitin C-terminal hydrolase-L1 proteins that are able to various compensatory signaling pathways driving tumor
induce doxorubicin resistance by elevating the level of P- growth and metastasis invariably become the underly-
gp.288 TDEs promote platinum resistance by upregulating ing cause of tumor refractoriness.301 Several preclinical
EMT markers and changing TGF-β/SMAD signaling path- and clinical studies have linked poor performance and
way in ovarian cancer cells, and exosomes from epithe- resistance to antiangiogenic agents to the activation of
lial ovarian cancer A2780 platinum-resistant cells attain a range of compensatory angiogenic signaling pathways
resistance via promoting EMT.289 Exosome-transmitted and various angiogenic factors that support the angio-
miR-567 reverses trastuzumab resistance in breast tumor genic bypass mechanism.302 The vascular endothelial
cells by inhibiting ATG5.290 In MDA-MB-231 and MCF- growth factor (VEGF)/VEGF receptor signaling path-
7 breast cancer cells, exosome-mediated miR-155 induces way is the most promising angiogenic target due to its
chemoresistance via upregulating EMT markers and tar- pivotal role in angiogenesis and tumor growth.303,304
geting CCAAT/enhancer-binding protein β (C/EBP-β), Previous studies have suggested that revascularization
TGF-β, and forkhead box O 3α (FOXO-3α) mRNA.291 In appears even after blocking VEGF signaling pathways
HER2-positive breast cancer, lncRNA-SNHG14 induces because of the activation of redundant angiogenic
exosome-mediated trastuzumab resistance by targeting the pathways.
LEI et al. 15 of 38

Serial evidence accumulated in recent years linked chemotherapy, targeted drug, or tumor vaccines have been
the function of various compensatory/alternative/bypass proposed and tested. Radiation can trigger an adaptive
angiogenic canonical mechanisms sustaining the pro- mechanism to increase the expression of PD-L1 on tumor
gression of cancers while exposed to antiangiogenic cells.312 Additionally, radiation may increase the depth
drugs.299,300,305 The current experimental, clinical, and and duration of immune responses by promoting a more
epidemiological data has definitely outlined at least four diverse adaptive antitumor immune response. As reported
potential different mechanisms, which can be considered by Victor et al., the combination of radiation with dual
for an explanation of evasive resistance to antiangiogenic checkpoint blockade (anti-CTLA-4 and anti-PD-1) can
therapies. The first mechanism refers to the activation enhance tumor control and survival in a preclinical model
and/or upregulation of compensatory pro-angiogenic sig- of melanoma, where radiation prime immune response
naling pathways within the cancer.306 The second mech- by increasing T cell receptor repertoire of intratumoral
anism is mainly driven by myeloid/stromal cells, which T cells and expanding peripheral clones.313 Combination
compensate for the requirement of the VEGF-mediated with chemotherapy aims to assist ICI treatment by releas-
pathway, thereby promoting tumor angiogenesis.305 The ing neoantigens or modulating the TME via depleting
third manner is attributed to the dual role of pericytes; Tregs and MDSCs.314 However, it has been reported that
first, in establishing the increased pericyte coverage of the efficacy of this combination therapy is model (cancer
the tumor vasculature, and second, their potential angio- type)-dependent and regimen-type-dependent. Combina-
genic attributes, both serving as escape mechanisms from tion with chemotherapeutic drugs is not always able to
VEGF-mediated angiogenesis.307 The fourth way is asso- tune the TME or enhanced antitumor efficacy. Even with
ciated with remodeling and accessing normal vasculature the effect of depleting MDSCs, the combination may
for the invasion and metastasis of tumors in lieu of obligate not be beneficial to enhance treatment responsiveness.314
neovascularization.306 Additional studies combining single agents with ICIs
As an important component of TME, the immune sys- are still required to better understand potential inter-
tem plays a critical role in regulating the response of actions between drugs and the heterogeneity of TME.
cancer cells to therapies, particularly immunotherapies. Compared to the less predictable ICI–chemotherapy com-
Immune-targeted therapies approved for cancer include bination, the combination of TME-targeted drugs with
monoclonal antibodies against immune checkpoints like immune checkpoint blockade is considered a relatively
cytotoxic T-lymphocyte-associated protein 4 (CTLA4), PD- logical approach to enhance the stimulation of antitu-
1, and programmed cell death ligand 1 (PD-L1), which mor immune response. TME-targeted therapies, such as
aim to modulate the antitumor T-cell immune response. angiogenesis inhibitors, stromal cell depletion agents,
The resistance to immune-checkpoint inhibitors (ICIs) has and immunomodulatory agents, can modulate the TME
been attributed to genomic and nongenomic mechanisms and enhance the immune response against the tumor.
that are influenced by the tumor–host–microenvironment Combining these agents with ICIs can lead to syner-
relationship.308 One mechanism is the upregulation of gistic effects of blocking inhibitory signals in T cells
alternative immune checkpoint pathways. Koyama et al. and activating the immune response, thereby improving
revealed that, in mouse xenograft models with lung adeno- treatment outcomes.315 For example, the VEGF inhibitor
carcinoma, other immune checkpoint proteins, including bevacizumab can augment intratumoral CD8+ T cell infil-
T-cell immunoglobulin mucin 3, lymphocyte activation tration through vascular normalization and endothelial
gene 3, and CTLA-4, were upregulated after PD-1 blockade cell activation, thereby potentiating PD-L1 checkpoint
therapy. The increased expression of alternative immune inhibition with PD-L1 inhibitor atezolizumab.316 This com-
checkpoints in PD-1 antibody-bound T cells can inhibit bination has shown promising anticancer efficacy and has
T cell activity and confer resistance to PD-1 blockade.309 been granted FDA approval for the treatment of patients
Other mechanisms include the presence of immunosup- with advanced unresectable or metastatic HCC.317
pressive cells, such as regulatory T cells (Tregs) or myeloid- Combining oncolytic vaccines with ICIs is an emerg-
derived suppressor cells (MDSCs), which can inhibit T ing approach to overcome ICI resistance. Oncolytic vac-
cell function.310 Besides, the presence of stromal cells in cines are a type of oncolytic virus that are engineered
TME, such as CAFs, has also been found to be associated to express tumor-specific antigens, which can stimulate
with suppressive CD8+ T cell infiltration and insensitivity an immune response against the cancer cells.318 As ICI-
to αPD-L1 antibody plus αCTLA-4 antibody dual immune resistant tumors are with a suppressed immune microenvi-
checkpoint blockade.311 ronment, the application of an oncolytic virus can reshape
Combination treatments appear to be the promis- TME and assist ICIs to boost the immune system leading to
ing strategy to overcome resistance to immune check- a stronger antitumor response.319 This combination ther-
point inhibitors. Combinations of ICIs with radiation, apy has shown promising results in preclinical and clinical
16 of 38 LEI et al.

studies in a variety of cancers, including melanoma, breast apy due to their ability to activate DNA damage repair
cancer, and bladder cancer.320–322 and antiapoptotic signaling pathways, which may lead to
Recent studies have shown that bacteria can reside incomplete tumor eradication and recurrence after treat-
within tumors and play a role in controlling cancer ment. Based on these findings, the researchers put forward
response to therapy by modulating the TME.323 For the “CSC theory” and found evidence of the existence of
example, Pseudomonas aeruginosa and Escherichia coli CSCs in some cancer tissues.336,337 CSCs can resist therapy
are two types of bacteria found to colonize tumors mainly because of the overexpression of MDR transporters
in various types of cancer, including lung, breast, and that mediate drug efflux, the more active DNA repair
pancreatic cancer.324–326 These bacteria can metabolize capacity, and the tendency to form new microvascular for
chemotherapy drugs such as gemcitabine, reducing their the tumor.338 These characteristics enable CSCs to tolerate
concentration within the tumor and rendering them treatment, maintain the tumor with nutrients and oxy-
less effective.327,328 Moreover, certain commensal bac- gen, and rapidly repopulate the tumor. This mechanism
teria or pathogens within the TME may interact with is similar to that of normal tissue stem cells in response
immune cells and alter the production of cytokines and to trauma, which may explain that the bladder CSCs
chemokines, which are involved in the immune response actively contribute to the cause of chemotherapy resis-
to cancer.329,330 The influence of gut microbiota on can- tance after several cycles of chemotherapy.339,340 Targeting
cer resistance has also gained extensive attention. A recent this trauma response of CSCs can become a new ther-
study found that in mice and patients with castration- apeutic intervention. CSCs between different treatment
resistant prostate cancer, an adaptive change in the gut cycles actively regenerate and respond to chemotherapy-
commensal microbiota was observed after ADT: There was induced injury or apoptosis, much as normal tissue stem
an expansion of commensal microbiota species that can cells respond to trauma-induced damage. Dying cells
convert androgen precursors to produce androgens, which release a metabolite called prostaglandin E2 (PGE2) that
were absorbed into the systemic circulation thus induc- stimulates proliferation and causes CSC to repopulate can-
ing castration or endocrine therapy resistance.331 This type cers shrunk by chemotherapy.341,342 In normal cells, this
of resistance could be delayed by applying antibiotics to is an integral part of the wound repair process, where
reduce gut microbiota or could be reversed by fecal micro- PGE2 induces the regeneration of tissue stem cells. Iron-
biota transplantation hormone-sensitive prostate cancer ically, PGE2 induces more CSC regeneration between
patients,331 implicating two possible ways to overcome chemotherapy cycles in cancers. An essential character-
bacterial-mediated resistance. Although using antibiotics istic of CSC is maintaining self-renewal ability, and the
can directly eradicate the bacteria within the TME, this mechanism may be one key factor in promoting can-
approach may have limitations due to the risk of antibiotic cer development and metastasis.343,344 CSC theory helps
resistance.328 Another approach is to develop drug deliv- people understand the occurrence and development of
ery systems specifically targeting the tumor cells while cancers. In addition, CSCs can activate signaling path-
avoiding bacterial-mediated metabolism.332,333 For exam- ways that promote cell survival and proliferation, such as
ple, nanotechnology-based drug delivery systems can be the Wnt/β-catenin and Notch pathways.345–347 Therefore,
engineered to release drugs only in the tumor cells, min- understanding the mechanisms underlying CSC-mediated
imizing the exposure of the drug to the bacteria.323,332 resistance to therapy is essential for developing effective
The presence of bacteria within the TME and possible cancer treatments. It provides a new perspective on cancer
influences from gut microbiota are thought to be signifi- development, metastasis, drug resistance, and recurrence.
cant factors contributing to treatment resistance in cancer. Leukemia therapy targeting LSC (leukemia stem cells) has
Understanding the complex interactions between bacte- achieved good clinical efficacy, and beneficial research has
ria and tumors is essential for developing effective cancer also been carried out in solid cancers.348
treatments to overcome this resistance. EMT is one of the essential mechanisms of cancer
metastasis. The latest research suggests that cancer cells
with dual characteristics of EMT and stem cells are the
2.8 Tumor plasticity key to cancer metastasis and drug resistance.349 There is
a direct link between EMT and CSCs, but the molecular
CSCs are a small population of cells within a tumor mechanism is still unclear. EMT phenomenon refers to
that possess stem cell–like properties and are thought a reversible process in which relatively stable epithelial
to be responsible for tumor initiation, growth, and cells lose cell polarity and intercellular adhesion and
metastasis.334,335 These cells have been identified in var- transform into spindle-shaped mesenchymal cells with
ious cancers, including breast, colon, and GBM. CSCs migration ability. It is ubiquitous in epithelial cancer
are less sensitive to chemotherapy and radiation ther- cells. Its essential feature is the loss of the expression of
LEI et al. 17 of 38

epithelial markers, such as E-cadherin, β-catenin, tight of prostate cancer failed with abiraterone/enzalutamide
junction protein, and epithelial cell adhesion molecules on therapy.370
the cell membrane of cancer cells,350–353 and meanwhile From the discussion above, it is evident that targeting
obtaining a mesenchymal phenotype with the increased EMT processes or cellular plasticity has great potential
expression of vimentin, N-cadherin, fibronectin, and β1 to circumvent drug resistance. However, only a few com-
and β3 integrins.354–356 The mechanism of EMT is mainly pounds adesigned to inhibit the EMT process are currently
due to changes in the epithelial cells themselves or the in clinical trials. Inhibitors targeting Notch, TGF-β, and
surrounding microenvironment, leading to the activation Wnt signaling pathways are also promising candidates for
of a series of signal transduction pathways, and related inhibiting EMT and cellular plasticity.371 TGF-β hetero-
transcription factors in the nucleus play a regulatory geneity in the cancer microenvironment creates rapidly
role.357 Precise intracellular signaling mechanisms reg- dividing CSCs that accelerate cancer growth and oth-
ulate different degrees of epithelial cell transformation. ers that invade surrounding healthy tissue and evade
Various extracellular signals activate different nuclear treatment.372,373 For example, PF-03446962 and galunis-
transcription factors by binding to specific receptors on ertib are antagonists designed to inhibit TGF-β receptors,
the cell surface. The common feature of these transcrip- currently in phase I clinical studies in solid cancers
tion factors is that they can recognize the DNA binding (NCT00557856, NCT02423343).374 Both PF-03446962 and
sequence of the E-box motif on the target gene promoter, galunisertib inhibit the EMT program, thereby preventing
thereby regulating the expression of the target gene cancer development. In addition, Wnt inhibitors such as
and initiating EMT.358 Loss of E-cadherin expression is ETC-1922159 and OMP-54F28 have been reported to inhibit
currently considered the most prominent feature of EMT. the EMT program and are currently in phase I clinical trials
Decreased E-cadherin levels can lead to decreased cell in cancer (NCT02521844, NCT01608867).375
adhesion and make cells easily invade and metastasize.351
Cancer cells lose some of the characteristics of epithelial
cells and acquire the characteristics of mesenchymal cells 3 PERSPECTIVES IN OVERCOMING
through EMT, so cancer cells can obtain stronger invasion CANCER RESISTANCE
and migration capabilities.359,360
Snail is involved in triggering EMT during the pro- Cancer chemotherapy is still a required treatment method
gression of epithelial cancers and is a crucial point for most cancer patients. However, cancer cells are prone to
in the occurrence of EMT. Snail expression correlates MDR, a significant problem limiting the efficacy of current
with the reduced loss of E-cadherin and acts as a direct chemotherapeutic drugs lacking selectivity. Many cancer
repressor of E-cadherin transcription.361 Twist is another patients have a remarkable curative effect in the early
essential transcription factor that regulates EMT. Its stage of chemotherapy. However, the drug resistance of
mechanism of inducing EMT is to directly or indirectly cancer cells increases with the prolongation of treatment
bind the E-cadherin promoter through the E-box motif, time, eventually leading to treatment failure. Anticancer
thereby inhibiting the expression of E-cadherin.362 strategies are constantly evolving, and targeted therapy
Snail/Twist1 knockout breast cancer model demonstrates drugs have encountered increasing resistance after the ini-
that chemotherapy resistance is associated with EMT.363 tial excitement, including primary and acquired resistance.
Studies have shown that EMT may be involved in drug Strategies to address drug resistance through combination
resistance of cancer cells, such as lung, pancreatic, and therapy have made some progress, although consider-
breast cancer.364–366 Numerous studies have shown able challenges have been faced, and the full potential of
that cancer cells develop resistance to carboplatin or combination therapy has not yet been realized.
paclitaxel by acquiring mesenchymal cell phenotype, According to statistics, in the early 1990s, the main
indicating that EMT may be the instigator of chemother- reasons for the failure of new drug development were con-
apy resistance.367,368 The latest research shows that centrated in poor pharmacokinetics and limited biological
cancers may have a type of partial EMT, which means activity.376,377 With the introduction of absorption, distri-
the cancer cells have both epithelial and mesenchymal bution, metabolism, and excretion for predictive analysis
cell phenotypes, and these cancer cells are more aggres- and research applications, the clinical failure rate dropped
sive than the others.368 EMT has been described as a from 40% to 10% in 2000.378 With the accumulation of basic
significant cause of EGFRi failure in EGFR-mutated research on targets and signaling pathways and the advent
NSCLC.369 Cellular transdifferentiation, a phenotypic of the era of genome sequences, the success rate of clini-
shift from adenocarcinoma to squamous cell carcinoma cal development of targeted drugs is also increasing. For
or neuroendocrine carcinoma, occurs in 3%–14% of example, the familiar TKIs have become one of the most
EGFR-mutant NSCLC patients, and approximately 17% popular research directions. In recent years, with a series
18 of 38 LEI et al.

of significant breakthroughs in technological applications, and moderate inhibitor of CYP450-3A4 and substantially
such as the application of high-throughput genomics to reduces the clearance of drugs such as other CYP450-
discover new targets,379,380 the identification of molecular 3A4 substrates.397 In the phase I clinical trial of lapatinib
biomarkers,381,382 and the progress of statistical methods and pazopanib, investigators compared the historical phar-
in biological and chemoinformatics,383,384 the progress and macokinetic parameters of the two drugs and concluded
the success rate of research and development have been that the drug combination did not alter drug exposure.398
greatly improved. However, new problems are still emerg- However, in a more detailed phase II pharmacokinetic
ing, with lacking clinical efficacy and increased toxicity analysis, the combination indicated a significant drug–
still the main directions of failure in the second research drug interaction contributing to the reduced efficacy of
and development phase. lapatinib in glioma patients.399,400 In addition, the frequent
Nanodrugs represent a promising approach to overcom- use of antiepileptic drugs in this patient population also
ing resistance to cancer. These drugs are engineered to reduced pazopanib exposure, resulting in poorer patient
be nanoscale size and have unique physicochemical prop- outcomes.401 This highlights the importance of detailed
erties that enable them to target cancer cells while min- pharmacokinetic assessment for the combined evaluation
imizing off-target effects.385 Nanodrugs can be designed of anticancer drugs. Combination therapies approved or
to overcome resistance by delivering drugs to cancer cells in clinical trials in the recent 5 years are summarized in
in more targeted and controlled manner and bypassing Table 1.
resistance mechanisms such as efflux pumps and DNA Antibodies, cytotoxic drugs, and conjugates bridge
repair pathways.386–388 One key advantage of nanodrugs ADC (antibody–drug–conjugates) drugs. The antibody will
is their ability to improve the pharmacokinetics and phar- specifically recognize and guide the drug to the lesion. The
macodynamics of drugs.386 By encapsulating drugs within conjugate can generally be broken in the pH environment
nanocarriers, the drug concentration within the tumor of the lesion site, thereby releasing the cytotoxin with a
can be increased, improving drug efficacy.332 Addition- therapeutic effect. Cytotoxins mainly target the DNA and
ally, nanocarriers can protect the drug from degradation tubulin of cancer cells, block the proliferation of tumor
and clearance, leading to a longer half-life and a sustained cells, and induce apoptosis.401,402 After the second new
drug release.386,389 Nanodrugs can also be engineered to ADC drug Adcetris (brentuximab vedotin) was approved
overcome specific resistance mechanisms. For example, by the FDA in 2011, 10 ADC drugs have been approved so
nanodrugs can target CSCs by incorporating specific lig- far, 7 of which have been approved in the last 3–4 years.
ands that bind to stem cell markers.390 Nanodrugs can ADC drugs can improve the selectivity of tumor treatment
also be engineered to overcome bacterial-mediated resis- and can better deal with the drug resistance of targeted
tance by releasing drugs only within the TME and avoiding monoclonal antibodies.403,404 It is considered one of the
bacterial exposure.328 By improving drug delivery, tar- essential directions for developing monoclonal antibodies
geting, and overcoming specific resistance mechanisms, (especially in the field of tumor-targeted therapy) in the
nanodrugs can potentially improve the efficacy of can- next decade. The tissue specificity and cytotoxicity of the
cer treatment and patient outcomes.391 However, further new generation of ADCs have been improved compared
research is needed to optimize the design and delivery with the previous generation products, allowing them to
of nanodrugs and to ensure their safety and efficacy in show fantastic activity in treating refractory cancers.405,406
clinical use. The currently available evidence shows that the potency
Polytherapy can make cancer cells less likely to develop of ADCs is based on complex and delicate interactions
compensatory resistance mechanisms than a single or among antibodies, conjugates, various components of the
sequential drug regimen. There are many problems in cytotoxin, and the tumor and its microenvironment.407
the reversal of MDR with combination drugs, including Combining ADCs with other antibody therapies, such as
clinical toxicity and pharmacokinetic interactions. The ADCs with the anti-VEGF monoclonal antibody beva-
therapeutic range of each drug may be narrow when cizumab, has also shown activity in preclinical models.408
administered in combination, and there may be an over- This may be due to bevacizumab’s enhanced drug delivery
lap in toxicity.392 In some cases, in addition to the efficiency by altering tumor vascular innervation.
expected overlapping toxicities, combination therapy has Some researchers proposed to reverse chemother-
some characteristic toxicities.393,394 We cannot accurately apy resistance by targeting inhibitor of apoptosis (IAP)
predict toxicity from preclinical models, which adds to inhibitors.409 The IAP protein family plays an essential role
the challenge of optimizing the toxicity–potency balance in controlling programmed cell death, and the expression
of drug combinations. Meanwhile, the pharmacokinetic level of IAP in cancer cells is significantly increased. There-
interaction is the question of how to combine two or fore, by directly or indirectly regulating the expression
more drugs.395,396 For example, lapatinib is a substrate of apoptotic proteins on the extrinsic apoptotic pathway
LEI et al. 19 of 38

TA B L E 1 Cancer combination therapies approved or in clinical trials in the recent 5 years.

Approval date/Clinical trials
Combination therapy Target cancer type process
Tremelimumab + durvalumab + platinum- Adult patients with metastatic NSCLC with no November 10, 2022
based sensitizing EGFR mutation or ALK genomic (NCT03164616)
chemotherapy cancer aberrations
Brentuximab Pediatric patients 2 years of age and older with November 10, 2022
vedotin + doxorubicin + vincristine + etopo- previously untreated high risk cHL (NCT03755804)
side + prednisone + cyclophosphamide
Cemiplimab-rwlc + platinum-based Adult patients with advanced NSCLC with no November 8, 2022
chemotherapy EGFR, ALK, or ROS1 aberrations (NCT03409614)
Tremelimumab + durvalumab Adult patients with uHCC October 21, 2022 (NCT03298451)
Durvalumab + gemcitabine + cisplatin Adult patients with locally advanced or September 2, 2022 (NCT03875235)
metastatic BTC
Darolutamide + docetaxel Adult patients with mHSPC August 5, 2022 (NCT02799602)
Dabrafenib + trametinib Adult and pediatric patients ≥6 years of age Accelerated Approval June 22,
with unresectable or metastatic solid 2022 (NCT02034110,
cancers with BRAF V600E mutation NCT02465060, NCT02124772,
original projected completion:
October 21, 2028)
Nivolumab + fluoropyrimidine- and Patients with advanced or metastatic ESCC May 27, 2022 (NCT03143153)
platinum-based chemotherapy
Nivolumab + ipilimumab Patients with advanced or metastatic ESCC May 27, 2022 (NCT03143153)
Ivosidenib + azacitidine (azacitidine for Newly diagnosed AML with a susceptible May 25, 2022 (NCT03173248)
injection) IDH1 mutation
Nivolumab + relatlimab-rmbw Adult and pediatric patients 12 years of age or March 18, 2022 (NCT03470922)
older with unresectable or metastatic
melanoma
Abatacept + a calcineurin Adults and pediatric patients 2 years of age December 15, 2022 (NCT
inhibitor + methotrexate and older undergoing HSCT 01743131)
Rituximab + chemotherapy Pediatric patients (≥6 months to <18 years) December 2, 2022 (NCT01516580)
with previously untreated, advanced stage,
CD20-positive DLBCL, BL, BLL, or mature
B-AL
Pembrolizumab + chemotherapy, with or Patients with persistent, recurrent, or October 13, 2021 (NCT03635567)
without bevacizumab metastatic cervical cancer whose cancers
express PD-L1
Lenvatinib + pembrolizumab Adult patients with advanced RCC August 10, 2021 (NCT02811861)
Pembrolizumab + chemotherapy as High-risk, early-stage, TNBC July 26, 2021 (NCT03036488)
neoadjuvant treatment, and then continued
as a single agent as adjuvant treatment after
surgery
Pembrolizumab + lenvatinib Patients with advanced endometrial carcinoma July 21, 2021 (NCT03517449)
Daratumumab + hyaluronidase- Adult patients with multiple myeloma July 9, 2022 (NCT03180736)
fihj + pomalidomide + dexamethasone
Patients with locally advanced unresectable or Accelerated Approval May 5,
Pembrolizumab + trastuzumab + fluoropyrimidine- metastatic HER2-positive gastric or GEJ 2021 (NCT03615326, original
and platinum-containing adenocarcinoma projected completion:
chemotherapy September 30, 2024)
Nivolumab + fluoropyrimidine- and Advanced or metastatic gastric cancer, GEJ, April 16, 2021 (NCT02872116)
platinum-containing chemotherapy and esophageal adenocarcinoma
Isatuximab- Adult patients with relapsed or refractory March 31, 2021 (NCT03275285)
irfc + carfilzomib + dexamethasone multiple myeloma
Pembrolizumab + platinum and Patients with metastatic or locally advanced March 22, 2021 (NCT03189719)
fluoropyrimidine-based chemotherapy GEJ carcinoma
(Continues)
20 of 38 LEI et al.

TA B L E 1 (Continued)
Approval date/Clinical trials
Combination therapy Target cancer type process
Melphalan flufenamide + dexamethasone Adult patients with relapsed or refractory Accelerated Approval February
multiple myeloma 26, 2021 (NCT02963493,
original projected completion:
February 28, 2022)
Nivolumab + cabozantinib Patients with advanced RCC January 22, 2021 (NCT03141177)
Selinexor + bortezomib + dexamethasone Adult patients with multiple myeloma December 18, 2020
(NCT03110562)
Margetuximab-cmkb + chemotherapy Adult patients with metastatic HER2-positive December 16, 2020
breast cancer (NCT02492711)
Naxitamab + granulocyte-macrophage Pediatric patients 1 year of age and older and Accelerated Approval November
colony-stimulating factor adult patients with relapsed or refractory 25, 2020 (NCT 03363373,
high-risk neuroblastoma in the bone or bone original projected completion:
marrow September 30, 2027)
Pembrolizumab + chemotherapy Patients with locally recurrent unresectable or November 13, 2020
metastatic TNBC (NCT02819518)
Venetoclax + azacitidine + decitabine Newly diagnosed AML in adults 75 years or October 16, 2020 (NCT02993523)
older
Nivolumab + ipilimumab Adult patients with unresectable malignant October 2, 2020 (NCT02899299)
pleural mesothelioma
Carfilzomib + daratumumab + dexamethasone Adult patients with relapsed or refractory August 20,2020 (NCT03158688)
multiple myeloma
Tafasitamab-cxix + lenalidomide Adult patients with relapsed or refractory Accelerated Approval July 31,
DLBCL 2020 (NCT02399085, original
projected completion:
December 31, 2025)
Atezolizumab + cobimetinib + vemurafenib Patients with BRAF V600 mutation-positive July 30, 2020 (NCT02908672)
unresectable or metastatic melanoma
Oral decitabine + cedazuridine Adult patients with MDS July 7, 2020 (NCT02103478)
Pertuzumab + trastuzumab + hyaluronidase– Patients with HER2-positive, locally advanced, June 29, 2020 (NCT03493854)
zzxf inflammatory, or early stage breast cancer
Ramucirumab + erlotinib Metastatic NSCLC with EGFR exon 19 May 29, 2020 (NCT02411448)
deletions or exon 21 mutations
Atezolizumab + bevacizumab Patients with unresectable or metastatic May 29, 2020 (NCT03434379)
hepatocellular carcinoma
Nivolumab + ipilimumab + 2 cycles of Patients with metastatic or recurrent NSCLC May 26, 2020 (NCT03215706)
platinum-doublet chemotherapy
Olaparib + bevacizumab Adult patients with advanced epithelial May 8, 2020 (NCT03737643)
ovarian, fallopian tube, or primary
peritoneal cancer
Ibrutinib + rituximab Adult patients with CLL or SLL April 21, 2020 (NCT02048813)
Tucatinib + trastuzumab + capecitabine Adult patients with advanced unresectable or April 17, 2020 (NCT02614794)
metastatic HER2-positive breast cancer
Encorafenib + cetuximab Adult patients with metastatic CRC with a April 8, 2020 (NCT02928224)
BRAF V600E mutation
Durvalumab + etoposide + either carboplatin Patients with ES-SCLC March 27, 2020 (NCT03043872)
or cisplatin
Nivolumab + ipilimumab Patients with HCC Accelerated Approval March 10,
2020 (NCT01658878, original
projected completion: July 31,
2024)
(Continues)
LEI et al. 21 of 38

TA B L E 1 (Continued)
Approval date/Clinical trials
Combination therapy Target cancer type process
Isatuximab- Adult patients with multiple myeloma March 2, 2020 (NCT02990338)
irfc + pomalidomide + dexamethasone
Neratinib + capecitabine Adult patients with advanced or metastatic February 25, 2020 (NCT01808573)
HER2-positive breast cancer
Atezolizumab + paclitaxel Adult patients with metastatic NSCLC December 3, 2019 (NCT02367781)
protein-bound + carboplatin
Daratumumab + bortezomib + thalido- Adult patients with multiple myeloma in September 26, 2019
mide + dexamethasone newly diagnosed (NCT02541383)
Pembrolizumab + lenvatinib Patients with advanced endometrial carcinoma September 17, 2019
(NCT02501096)
Selinexor + dexamethasone Adult patients with RRMM July 3, 2019 (NCT02336815)
Daratumumab + lenalidomide + dexametha- Patients with newly diagnosed multiple June 27, 2019 (NCT02252172)
sone myeloma
Polatuzumab vedotin-piiq + bendamustine + a Adult patients with relapsed or refractory Accelerated Approval June 10,
rituximab product DLBCL 2019 (NCT02257567, original
projected completion: June 30,
2024)
Lenalidomide + a rituximab product Previously treated FL and previously treated May 28, 2019 (NCT01996865)
MZL
Alpelisib + fulvestrant Postmenopausal women, and men, with May 24, 2019 (NCT02437318)
HR-positive, HER2-negative,
PIK3CA-mutated, advanced or metastatic
breast cancer
Avelumab + axitinib Patients with advanced RCC May 14, 2019 (NCT02684006)
Atezolizumab + carboplatin + etoposide Adult patients with ES-SCLC March 18, 2019 (NCT02763579)
Glasdegib + low-dose cytarabine Newly diagnosed AML in patients who are 75 November 21, 2018
years old or older (NCT01546038)
Brentuximab vedotin + chemotherapy Previously untreated sALCL or other PTCL November 16, 2018
(NCT01777152)
Pembrolizumab + carboplatin + either Metastatic squamous NSCLC October 30, 2018 (NCT02775435)
paclitaxel or nab-paclitaxel
Pembrolizumab + pemetrexed + platinum Patients with metastatic, non-squamous August 20, 2018 (NCT02578680)
NSCLC
Ribociclib + an aromatase inhibitor Pre/perimenopausal women with HR-positive, July 18, 2018 (NCT02278120)
HER2-negative advanced or metastatic
breast cancer
Ribociclib + fulvestrant Postmenopausal women with HR-positive, July 18, 2018 (NCT02278120)
HER2-negative advanced or metastatic
breast cancer
Ipilimumab + nivolumab Patients 12 years of age and older with Accelerated Approval July 10,
metastatic CRC 2018 (NCT02060188, original
projected completion: July 31,
2024)
Encorafenib + binimetinib Patients with unresectable or metastatic June 27, 2018 (NCT01909453)
melanoma with a BRAF V600E or V600K
mutation
Bevacizumab + carboplatin + paclitaxel Patients with epithelial ovarian, fallopian tube, June 13, 2018 (NCT00262847)
or primary peritoneal cancer
(Continues)
22 of 38 LEI et al.

TA B L E 1 (Continued)
Approval date/Clinical trials
Combination therapy Target cancer type process
Dabrafenib + trametinib for the adjuvant Patients with melanoma with BRAF V600E or April 30, 2018 (NCT01682083)
treatment V600K mutations
Nivolumab + ipilimumab Previously untreated advanced renal cell April 16, 2018 (NCT02231749)
carcinoma
Abiraterone acetate tablets + prednisone Metastatic high-risk castration-sensitive February 7, 2018 (NCT01715285)
prostate cancer
Pertuzumab + trastuzumab + chemotherapy Patients with HER2-positive early breast December 20, 2017
cancer (NCT01358877)
Dabrafenib + trametinib Patients with metastatic NSCLC with BRAF June 22, 2017 (NCT01336634)
V600E mutation
Abbreviations: ALK, anaplastic lymphoma kinase; AML, acute myeloid leukemia; B-AL, B-cell acute leukemia; BL, Burkitt’s lymphoma; BLL, Burkitt-like lym-
phoma; BRAF, B-raf proto-oncogene; BTC, biliary tract cancer; cHL, classic Hodgkin lymphoma; CLL, chronic lymphocytic leukemia; CRC, colorectal cancer;
DLBCL, diffuse large B cell lymphoma; EGFR, epidermal growth factor receptor; ESCC, esophageal squamous cell carcinoma; ES-SCLC, extensive-stage small cell
lung cancer; GEJ, gastroesophageal junction adenocarcinoma; HER2, human epidermal growth factor receptor 2; HSCT, hematopoietic stem cell transplantation;
IDH1, isocitrate dehydrogenase 1; MDS, myelodysplastic syndromes; mHSPC, metastatic hormone-sensitive prostate cancer; MZL, marginal zone lymphoma;
NSCLC, non-small cell lung cancer; PD-L1, programmed cell death ligand 1; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha;
PTCL, peripheral T-cell lymphoma; RCC, renal cell carcinoma; ROS1, proto-oncogene 1; RRMM, relapsed or refractory multiple myeloma; sALCL, systemic
anaplastic large cell lymphoma; SLL, small lymphocytic lymphoma; TNBC, triple-negative breast cancer; uHCC, unresectable hepatocellular carcinoma.
Sources: Data from ClinicalTrials.gov.

(transmembrane apoptotic pathway)410 and the intrinsic ple anticancer drugs and improve the therapeutic effect
apoptotic pathway (mitochondrial apoptotic pathway),411 through synergistic therapeutic effects.414,420 Combining
the chemosensitivity of cell apoptosis can be improved and chemotherapeutics and MDR-reversing agents using a
obtained a potential response. However, the current com- drug delivery system has been a promising strategy for
bination of this method and chemotherapy only targets a reversing MDR in recent years.421–423 Common nano-
small number of tumor cells, and there are cases where drug carriers that have been reported to be used for
tumor cells are resistant to IAP inhibitors.412 the co-delivery of drugs include liposomes, nanoparticles,
The technologies for reversing tumor MDR at the gene micelles, nano-emulsions, and nanogels.424 Combining
level mainly include antisense nucleic acid technology,413 MDR drug reversal agents, RNAi/DNA, targeted drugs
ribozyme technology,414 and RNA interference (RNAi) with nanocarrier drug delivery systems, through non-
technology.415,416 Drugs that regulate miRNA expression specific internalization, reduce the efflux of drugs by
(such as miR-125, −20, −24) may have specific clini- ABC transporters in tumor cells, increases the uptake of
cal application prospects in reversing tumor MDR.417,418 drugs, and through RNAi/DNA Delivery, active target-
Although many constructed-cell line banks exist, the ing, and increased responsiveness to physiological stimuli
genetic characterization of these cells and human tumor can reverse tumor cell MDR.425–427 Combination types
samples varies enormously.419 Researchers are attempting of drugs delivered in combination include chemothera-
to create patient-derived cell culture models and then test peutics and chemotherapeutics,428,429 chemotherapeutics
these models on pharmacogenomics platforms to rapidly and MDR reversal agents,424,430,431 chemotherapy drugs
discover multiple effective drug combinations.418,419 These and siRNA,432–434 chemotherapy drugs and monoclonal
models can better reflect the biological complexity of antibodies.425,435 Among them, combining chemotherapy
human drug-resistant tumor cells than constructed cell and other drugs is the most common type of combination
models. However, the combination therapy results still administration.423 The rapid development of nano-drug
need to be verified by randomized clinical trials. delivery carriers provides a good carrier platform for
The study of functional drug delivery systems that improving the therapeutic effect of drugs and overcoming
can reverse tumor MDR will have broad application the MDR problem of tumors. Combining drug adminis-
prospects in improving the efficacy of chemotherapy tration with nano-drug carriers can enhance the effect of
drugs and reducing side effects.395 Due to tumors’ het- reversing MDR through various forms and achieve a sub-
erogeneity and drug resistance, it is usually challenging stantial combined effect by co-delivering different types
to achieve an excellent therapeutic effect using one drug of drugs. Nano-drug carrier-mediated co-administration
alone. Therefore, people have been devoting themselves is a promising strategy for reversing tumor MDR. Cur-
to designing nanocarriers that can be loaded with multi- rently, there is more and more research on reversing
LEI et al. 23 of 38

F I G U R E 4 Overcoming drug resistance in cancer. The purpose of overcoming the drug resistance of cancer cells is to optimize the
sensitivity of the therapy. This can be achieved by polytherapy using the combination of at least two drugs; immunotherapy using checkpoint
inhibitors or monoclonal antibodies; antibody–drug–conjugates improving the selectivity of cancer treatment; gene technology modifying the
epigenetic sequence; targeted therapy targeting the overexpression of drug efflux transporter or vital proteins for the cancer cell apoptosis;
and nanoparticle delivery system improving the efficacy of the drug and reducing the side effect. Source: This figure was created with
Biorender.com.

MDR of tumors by combined administration of nano-drug study the importance of proteins in intracellular signal-
carriers.419,436 With the clinical application of nanocarrier ing networks and explore the possibility of reversing tumor
drug delivery system, this technology shows great potential drug resistance based on the differential effects of drug
in reversing tumor MDR. targets on intracellular associations.439
Tumor immunotherapy can improve tumor patients’ The new technologies, for example, the novel compu-
immune function, kill or inhibit tumor cells, and reverse tational method, can be used for predicting polytherapy
tumor MDR with little adverse reactions. There are many switching strategies to overcome tumor heterogene-
studies on tumor immunohistology, enzymology, and ity and evolution. In addition, the widely used gene
cytokines,437,438 but most are still experimental research. silencing tools, including shRNA and CRISPR, could
Among them, the systems biology approach involves the help researchers propose and predict effective drug
analysis of large amounts of data, including genetics, effects both in vitro and in vivo. Finally, the clinical trial
transcriptomics, proteomics, or factors affecting posttrans- designs that reflect drug toxicity and utilize intermit-
lational regulation. Some systems’ biology approaches tent doses and adaptive trial designs that give dynamic
24 of 38 LEI et al.

TA B L E 2 Typical resistance mechanisms in cancer and combating strategies.

Resistance
mechanisms Combating strategies Typical example
Drug inactivation Drug replacement or Nucleoside analog phosphate prodrugs could bypass DCK
combination with enzyme deficiency-mediated AraC resistance in AML without the
enhancer demand for DCK phosphorylation36 or combination with
etoposide-enhancing DCK activity39
Drug detoxification Combination with metabolism GSTP1-1 inhibitor MC3181 could be used to reverse the
enzyme inhibitor vemurafenib resistance in melanoma80,81
Reduced drug Modulation of the cell membrane Cancer cell membrane–based biomimetic nanoparticle delivery
uptake lipid composition to increase systems could improve therapeutic efficacy for various MDR
permeability and fluidity cancers103–105
Increased drug Drug replacement, combination Targeted anticancer drugs, such as tepotinib and poziotinib, could
efflux with ABC transporter inhibit ABCB1 and ABCG2 to reverse the resistance to ABCB1
inhibitor, or silence of the and ABCG2 substrates128–130
efflux transporters
Mutation of drug Development of new generation EAI045 is the first allosteric EGFR TKI designed to overcome the
targets or multitarget anticancer drug acquired resistance mediated by T790M and C797S mutations147
DNA damage repair Combination with DNA repair ERK or p38 kinase inhibitors could overcome the resistance
inhibitor mediated by 5-FU-induced ERCC1 overexpression198
Blocked apoptosis Combination with apoptosis Navitoclax could trigger the resistance in CLL by inhibiting Bcl-2 to
inducer induce apoptosis219
Autophagy Combination with autophagy Imatinib combined with siRNAs targeting ATGs could potentiate
induction modulators the cytotoxicity and reverse the acquired resistance in both GIST
and CML233
Cell death Ferroptosis and cuproptosis Cellular ferroptosis and cuproptosis could sensitize chemotherapy
inhibition induction resistance in various cancers239–242
Tumor microenvi- Combination with inhibitors Inhibition of the β1 integrin activity by monoclonal antibody AIIB2
ronment targeting the specific protein could promote radiotherapy efficacy and elevates sensitivity to
function in TME HER2-targeting agents of breast cancer cells265,266
Cancer stem cell Development of novel drugs PF-03446962 is designed to inhibit TGF-β receptors resulting in the
targeting cancer stem cells antagonization of CSC division374
Epithelial-to- Development of novel drugs Inhibitors targeting Notch, TGF-β, and Wnt signaling pathways are
mesenchymal targeting the EMT process promising candidates for inhibiting EMT371
transition
Immunotherapy Combination with radiation, VEGF inhibitor bevacizumab can augment intratumoral CD8+ T
and immune chemotherapy, targeted drug, cell infiltration and endothelial cell activation, thereby
responses or tumor vaccines potentiating PD-L1 checkpoint inhibition with PD-L1 inhibitor
atezolizumab316,317
Abbreviations: 5-FU, 5-fluorouracil; ABC, ATP-binding cassette; ATG, autophagy-related gene; Bcl-2, B-cell lymphoma 2; CLL, chronic lymphocytic leukemia;
CML, chronic myeloid leukemia; CSC, cancer stem cell; DCK, deoxycytidine kinase; EGFR, epidermal growth factor receptor; EMT, epithelial–mesenchymal
transition; ERCC, excision repair cross-complementing 1; ERK, extracellular signal-regulated kinase; GIST, gastrointestinal stromal tumors; GSTP1, glutathione-
S-transferase Pi 1; HER2, human epidermal growth factor receptor 2; MDR, multidrug resistance; PD-L1, programmed cell death ligand 1; TGF-β, transforming
growth factor beta; TKI, tyrosine kinase inhibitor; TME, tumor microenvironment; VEGF, vascular endothelial growth factor.

combinations after the emergence of resistance will efflux, target alteration, cancer cell death inhibition, DNA
significantly accelerate the development of more effective damage repair, cellular heterogeneity, and more. Tumor
therapeutic combinations to reverse the MDR in cancer drug resistance has become a significant problem in oncol-
cells (Figure 4). ogy, affecting the treatment effect and prognosis of cancer
patients, and may lead to tumor progression or even recur-
rence. Therefore, it becomes crucial to understand the
4 CONCLUSION causes and underlying mechanisms of cancer drug resis-
tance, which will facilitate the development of various
As summarized in Table 2, MDR in cancer is a multi- therapies or combinations for treating different cancers.
factorial phenomenon that results in drug inactivation, Combination therapy is considered the most important
LEI et al. 25 of 38

treatment option for personalized medicine and overcom- 2. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020:
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Radiat Biol. 2020;96(9):1087-1103.
Zhe-Sheng Chen, Yihang Pan, and Leli Zeng designed the 6. Bedard PL, Hyman DM, Davids MS, Siu LL. Small molecules,
review. Zi-Ning Lei, Qin Tian, and Qiu-Xu Teng did the lit- big impact: 20 years of targeted therapy in oncology. Lancet.
erature search and wrote the manuscript. Zi-Ning Lei and 2020;395(10229):1078-1088.
Qiu-Xu Teng prepared the table and figures. Zhe-Sheng 7. Szostakowska M, Trebinska-Stryjewska A, Grzybowska EA,
Chen, Yihang Pan, and John N. D. Wurpel reviewed and Fabisiewicz A. Resistance to endocrine therapy in breast can-
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and approved the article.
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AC K N OW L E D G M E N T S 9. Bueschbell B, Caniceiro AB, Suzano PMS, Machuqueiro M,
This work is funded by the National Natural Science Foun- Rosario-Ferreira N, Moreira IS. Network biology and artifi-
dation of China (32270815), the National Key Research cial intelligence drive the understanding of the multidrug
resistance phenotype in cancer. Drug Resist Updat. 2022;60:
and Development Program of China #2018YFA0902801,
100811.
the 100 Top Talents Program of Sun Yat-sen Univer-
10. Turajlic S, Furney SJ, Stamp G, et al. Whole-genome sequenc-
sity (ZSQYBRJH0001), and Guangdong Basic and Applied ing reveals complex mechanisms of intrinsic resistance to
Basic Research Foundation #2021A1515010117. Z.N.L. and BRAF inhibition. Ann Oncol. 2014;25(5):959-967.
Q.X.T. appreciate the scholarship from the Department of 11. Ma Y, Wang L, Neitzel LR, et al. The MAPK pathway regulates
Pharmaceutical Sciences, College of Pharmacy and Health intrinsic resistance to BET inhibitors in colorectal cancer. Clin
Sciences, St. John’s University. We would like to acknowl- Cancer Res. 2017;23(8):2027-2037.
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Sheng Chen is the Editorial Board Member of MedComm. 14. Saleh R, Elkord E. Acquired Resistance to Cancer Immunother-
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