An RNA damage response network mediates the lethality of 5-FU in colorectal cancer
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.
Authors
- Kebing Yu
- Donald S. Kirkpatrick (ORCID: https://orcid.org/0000-0003-3091-2804)
- Matthew G. Vander Heiden (ORCID: https://orcid.org/0000-0002-6702-4192)
- Jung-Kuei Chen (ORCID: https://orcid.org/0000-0003-4964-2031)
- Karl A. Merrick (ORCID: https://orcid.org/0000-0002-7374-8429)
- Erika D. Handly (ORCID: https://orcid.org/0000-0001-8788-3050)
- Jonathan M. Hernandez (ORCID: https://orcid.org/0000-0001-7529-0557)
- George Eng (ORCID: https://orcid.org/0000-0003-4960-4705)
- Ian G. Cannell (ORCID: https://orcid.org/0000-0001-5832-9210)
- Adam C. Palmer (ORCID: https://orcid.org/0000-0001-5028-7028)
- Haeun Hwangbo (ORCID: https://orcid.org/0000-0002-3687-4282)
- Anita Izrael-Tomasevic
- Michael B. Yaffe (ORCID: https://orcid.org/0000-0002-9547-3251)
- Christopher M. Rose (ORCID: https://orcid.org/0000-0002-7502-3368)
- Aaron M. Hosios (ORCID: https://orcid.org/0000-0002-7702-5877)
- Anh Dinh
- Jesse C. Patterson (ORCID: https://orcid.org/0000-0003-1951-7803)
- Yi Wen Kong (ORCID: https://orcid.org/0000-0002-4223-971X)
- Lucía Suárez-López (ORCID: https://orcid.org/0000-0002-3719-0536)
- Ömer Yılmaz (ORCID: https://orcid.org/0000-0002-0962-2725)
Institutions
- University of North Carolina at Chapel Hill (US)
- National Institutes of Health (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- National Cancer Institute (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-10-01
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101778
- Citations
- 32
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 7.48
Funders
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology