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Identification of inhibitors synergizing gemcitabine sensitivity in the squamous subtype of pancreatic ductal adenocarcinoma (PDAC)

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Abstract

Pancreatic adenocarcinoma (PDAC) is a highly aggressive cancer with a high chance of recurrence, limited treatment options, and poor prognosis. A recent study has classified pancreatic cancers into four molecular subtypes: (1) squamous, (2) immunogenic, (3) pancreatic progenitor and (4) aberrantly differentiated endocrine exocrine. Among all the subtypes, the squamous subtype has the worst prognosis. This study aims to utilize large scale genomic datasets and computational systems biology to identify potential drugs targeting the squamous subtype of PDAC through combination therapy. Using the transcriptomic data available from the International Cancer Genome Consortium, Cancer Cell Line Encyclopedia and Connectivity Map, we identified 26 small molecules that could target the squamous subtype of PDAC. Among them include inhibitors targeting the SRC proto-oncogene (SRC) and the mitogen-activated protein kinase kinase 1/2 (MEK1/2). Further analyses demonstrated that the SRC inhibitors (dasatinib and PP2) and MEK1/2 inhibitor (pimasertib) synergized gemcitabine sensitivity specifically in the squamous subtype of PDAC cells (SW1990 and BxPC3), but not in the PDAC progenitor cells (AsPC1). Further analysis revealed that the synergistic effects are dependent on SRC or MEK1/2 activities, as overexpression of SRC or MEK1/2 completely abrogated the synergistic effects SRC inhibitors (dasatinib and PP2) and MEK1/2 inhibitor (pimasertib). In contrast, no significant toxicity was observed in the MRC5 human lung fibroblast and ARPE-19 human retinal pigment epithelial cells. Together, our findings suggest that combinations of SRC or MEK inhibitors with gemcitabine possess synergistic effects on the squamous subtype of PDAC cells and warrant further investigation.

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Acknowledgements

This work was supported in part by the Malaysia Ministry of Education Fundamental Research Grant Scheme (FRGS/1/2017/SKK08/IMU/03/1 to MCW, FFLC and COL; FRGS/1/2016/SKK08/IMU/01/1 to LWH) and the IMU Research Fund (BP I-01/14(05)2017; JLE, PNG, CYL and YJT).

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Authors and Affiliations

  1. School of Pharmacy, International Medical University, 126 Jalan 19/155B, 57000, Bukit Jalil, Kuala Lumpur, Malaysia

    Jia Lin Er, Pei Ni Goh, Chen Yuan Lee, Ying Jie Tan, Ling-Wei Hii, Chun Wai Mai & Chee-Onn Leong

  2. Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI), International Medical University, 57000, Bukit Jalil, Kuala Lumpur, Malaysia

    Ling-Wei Hii, Chun Wai Mai, Felicia Fei-Lei Chung & Chee-Onn Leong

  3. Mechanisms of Carcinogenesis Section (MCA), Epigenetics Group (EGE), International Agency for Research on Cancer World Health Organization, 150 Cours Albert Thomas, 69372, Lyon CEDEX 08, France

    Felicia Fei-Lei Chung

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  1. Jia Lin Er
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Er, J.L., Goh, P.N., Lee, C.Y. et al. Identification of inhibitors synergizing gemcitabine sensitivity in the squamous subtype of pancreatic ductal adenocarcinoma (PDAC). Apoptosis 23, 343–355 (2018). https://doi.org/10.1007/s10495-018-1459-6

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