An RNA damage response network mediates the lethality of 5-FU in colorectal cancer

Cell Rep Med. 2024 Oct 15;5(10):101778. doi: 10.1016/j.xcrm.2024.101778. Epub 2024 Oct 7.

Authors

Jung-Kuei Chen¹, Karl A Merrick¹, Yi Wen Kong¹, Anita Izrael-Tomasevic², George Eng¹, Erika D Handly³, Jesse C Patterson¹, Ian G Cannell¹, Lucia Suarez-Lopez¹, Aaron M Hosios⁴, Anh Dinh¹, Donald S Kirkpatrick², Kebing Yu², Christopher M Rose², Jonathan M Hernandez⁵, Haeun Hwangbo⁶, Adam C Palmer⁷, Matthew G Vander Heiden⁸, Ömer H Yilmaz⁴, Michael B Yaffe⁹

Affiliations

¹ Center for Precision Cancer Medicine, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
² Genentech Biotechnology company, South San Francisco, CA 94080, USA.
³ Center for Precision Cancer Medicine, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ Center for Precision Cancer Medicine, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁵ Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁶ Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pharmacology, Computational Medicine Program, UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷ Department of Pharmacology, Computational Medicine Program, UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁸ Center for Precision Cancer Medicine, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
⁹ Center for Precision Cancer Medicine, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Surgery, Beth Israel Medical Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: myaffe@mit.edu.

Abstract

5-fluorouracil (5-FU), a major anti-cancer therapeutic, is believed to function primarily by inhibiting thymidylate synthase, depleting deoxythymidine triphosphate (dTTP), and causing DNA damage. Here, we show that clinical combinations of 5-FU with oxaliplatin or irinotecan show no synergy in human colorectal cancer (CRC) trials and sub-additive killing in CRC cell lines. Using selective 5-FU metabolites, phospho- and ubiquitin proteomics, and primary human CRC organoids, we demonstrate that 5-FU-mediated CRC cell killing primarily involves an RNA damage response during ribosome biogenesis, causing lysosomal degradation of damaged rRNAs and proteasomal degradation of ubiquitinated ribosomal proteins. Tumor types clinically responsive to 5-FU treatment show upregulated rRNA biogenesis while 5-FU clinically non-responsive tumor types do not, instead showing greater sensitivity to 5-FU's DNA damage effects. Finally, we show that treatments upregulating ribosome biogenesis, including KDM2A inhibition, promote RNA-dependent cell killing by 5-FU, demonstrating the potential for combinatorial targeting of this ribosomal RNA damage response for improved cancer therapy.

Keywords: 5-FU; 5-FU-based chemotherapy; RNA damage; ribosomal RNA; ribosomal protein.

MeSH terms

Cell Line, Tumor
Colorectal Neoplasms* / drug therapy
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / metabolism
Colorectal Neoplasms* / pathology
DNA Damage* / drug effects
Fluorouracil* / pharmacology
Humans
Irinotecan / pharmacology
Jumonji Domain-Containing Histone Demethylases / genetics
Jumonji Domain-Containing Histone Demethylases / metabolism
Oxaliplatin / pharmacology
RNA, Ribosomal* / genetics
RNA, Ribosomal* / metabolism
Ribosomes / drug effects
Ribosomes / metabolism

Substances

Fluorouracil
RNA, Ribosomal
Jumonji Domain-Containing Histone Demethylases
Irinotecan
Oxaliplatin