An RNA Damage Response Network Mediates the Lethality of 5-FU in Clinically Relevant Tumor Types.

Autor:	Chen JK; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Merrick KA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Kong YW; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Izrael-Tomasevic A; Genentech Biotechnology company, South San Francisco, CA 94080, USA., Eng G; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Handly ED; 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., Patterson JC; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Cannell IG; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Suarez-Lopez L; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Hosios AM; 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., Dinh A; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Kirkpatrick DS; Genentech Biotechnology company, South San Francisco, CA 94080, USA., Yu K; Genentech Biotechnology company, South San Francisco, CA 94080, USA., Rose CM; Genentech Biotechnology company, South San Francisco, CA 94080, USA., Hernandez JM; Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Hwangbo H; Curriculum in Bioinformatics and Computational Biology, UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Department of Pharmacology, Computational Medicine Program, and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Palmer AC; Department of Pharmacology, Computational Medicine Program, and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Vander Heiden MG; 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., Yilmaz ÖH; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Yaffe MB; 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.; Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Apr 29. Date of Electronic Publication: 2023 Apr 29.
DOI:	10.1101/2023.04.28.538590
Abstrakt:	5-fluorouracil (5-FU) is a successful and broadly used anti-cancer therapeutic. A major mechanism of action of 5-FU is thought to be through thymidylate synthase (TYMS) inhibition resulting in dTTP depletion and activation of the DNA damage response. This suggests that 5-FU should synergize with other DNA damaging agents. However, we found that combinations of 5-FU and oxaliplatin or irinotecan failed to display any evidence of synergy in clinical trials, and resulted in sub-additive killing in a panel of colorectal cancer (CRC) cell lines. In seeking to understand this antagonism, we unexpectedly found that an RNA damage response during ribosome biogenesis dominates the drug's efficacy in tumor types for which 5-FU shows clinical benefit. 5-FU has an inherent bias for RNA incorporation, and blocking this greatly reduced drug-induced lethality, indicating that accumulation of damaged RNA is more deleterious than the lack of new RNA synthesis. Using 5-FU metabolites that specifically incorporate into either RNA or DNA revealed that CRC cell lines and patient-derived colorectal cancer organoids are inherently more sensitive to RNA damage. This difference held true in cell lines from other tissues in which 5-FU has shown clinical utility, whereas cell lines from tumor tissues that lack clinical 5-FU responsiveness typically showed greater sensitivity to the drug's DNA damage effects. Analysis of changes in the phosphoproteome and ubiquitinome shows RNA damage triggers the selective ubiquitination of multiple ribosomal proteins leading to autophagy-dependent rRNA catabolism and proteasome-dependent degradation of ubiquitinated ribosome proteins. Further, RNA damage response to 5-FU is selectively enhanced by compounds that promote ribosome biogenesis, such as KDM2A inhibitors. These results demonstrate the presence of a strong RNA damage response linked to apoptotic cell death, with clear utility of combinatorially targeting this response in cancer therapy.
Databáze:	MEDLINE
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