Nucleotide excision repair deficiency is a targetable therapeutic vulnerability in clear cell renal cell carcinoma.

Due to a demonstrated lack of DNA repair deficiencies, clear cell renal cell carcinoma (ccRCC) has not benefitted from targeted synthetic lethality-based therapies. We investigated whether nucleotide excision repair (NER) deficiency is present in an identifiable subset of ccRCC cases that would render those tumors sensitive to therapy targeting this specific DNA repair pathway aberration. We used functional assays that detect UV-induced 6-4 pyrimidine-pyrimidone photoproducts to quantify NER deficiency in ccRCC cell lines. We also measured sensitivity to irofulven, an experimental cancer therapeutic agent that specifically targets cells with inactivated transcription-coupled nucleotide excision repair (TC-NER). In order to detect NER deficiency in clinical biopsies, we assessed whole exome sequencing data for the presence of an NER deficiency associated mutational signature previously identified in ERCC2 mutant bladder cancer. Functional assays showed NER deficiency in ccRCC cells. Some cell lines showed irofulven sensitivity at a concentration that is well tolerated by patients. Prostaglandin reductase 1 (PTGR1), which activates irofulven, was also associated with this sensitivity. Next generation sequencing data of the cell lines showed NER deficiency-associated mutational signatures. A significant subset of ccRCC patients had the same signature and high PTGR1 expression. ccRCC cell line-based analysis showed that NER deficiency is likely present in this cancer type. Approximately 10% of ccRCC patients in the TCGA cohort showed mutational signatures consistent with ERCC2 inactivation associated NER deficiency and also substantial levels of PTGR1 expression. These patients may be responsive to irofulven, a previously abandoned anticancer agent that has minimal activity in NER-proficient cells.

Scientific reports. 2023 Nov 23*** epublish ***

Aurel Prosz, Haohui Duan, Viktoria Tisza, Pranshu Sahgal, Sabine Topka, Gregory T Klus, Judit Börcsök, Zsofia Sztupinszki, Timothy Hanlon, Miklos Diossy, Laura Vizkeleti, Dag Rune Stormoen, Istvan Csabai, Helle Pappot, Joseph Vijai, Kenneth Offit, Thomas Ried, Nilay Sethi, Kent W Mouw, Sandor Spisak, Shailja Pathania, Zoltan Szallasi

Danish Cancer Institute, Copenhagen, Denmark., Center for Personalized Cancer Therapy, University of Massachusetts, Boston, MA, USA., Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA., Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Department of Bioinformatics, Semmelweis University, Budapest, Hungary., Department of Oncology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark., Department of Physics of Complex Systems, Eötvös Loránd University, Budapest, Hungary., Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen, Denmark., Institute of Enzymology, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary. ., Center for Personalized Cancer Therapy, University of Massachusetts, Boston, MA, USA. ., Danish Cancer Institute, Copenhagen, Denmark. .