Cisplatin-based chemotherapy is a first-line treatment for muscle-invasive and metastatic urothelial cancer. Approximately 10% of bladder urothelial tumors have a somatic missense mutation in the nucleotide excision repair (NER) gene ERCC2, which confers increased sensitivity to cisplatin-based chemotherapy.
However, a significant subset of patients is ineligible to receive cisplatin-based therapy due to medical contraindications, and no NER-targeted approaches are available for platinum-ineligible or platinum-refractory ERCC2 mutant cases.
We use a series of NER proficient and NER deficient preclinical tumor models to test sensitivity to irofulven, an abandoned anti-cancer agent. In addition, we use available clinical and sequencing data from multiple urothelial tumor cohorts to develop and validate a composite mutational signature of ERCC2 deficiency and cisplatin sensitivity.
We identify a novel synthetic lethal relationship between tumor NER deficiency and sensitivity to irofulven. Irofulven specifically targets cells with inactivation of the transcription-coupled NER (TC-NER) pathway and leads to robust responses in vitro and in vivo, including in models with acquired cisplatin resistance, while having minimal effect on cells with intact NER. We also find that a composite mutational signature of ERCC2 deficiency is strongly associated with cisplatin response in patients and is also associated with cisplatin and irofulven sensitivity in preclinical models.
Tumor NER deficiency confers sensitivity to irofulven, a previously abandoned anti-cancer agent with minimal activity in NER proficient cells. A composite mutational signature of NER deficiency may be useful in identifying patients likely to respond to NER-targeting agents including cisplatin and irofulven.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020 Nov 18 [Epub ahead of print]
Judit Börcsök, Zsofia Sztupinszki, Raie Bekele, Sizhi P Gao, Miklos Diossy, Amruta S Samant, Kasia M Dillon, Viktoria Tisza, Sándor Spisák, Orsolya Rusz, Istvan Csabai, Helle Pappot, Zoe J Frazier, David J Konieczkowski, David Liu, Naresh Vasani, James A Rodrigues, David B Solit, Jean H Hoffman-Censits, Elizabeth R Plimack, Jonathan E Rosenberg, Jean-Bernard Lazaro, Mary-Ellen Taplin, Gopa Iyer, Søren Brunak, Rita Lozsa, Eliezer M Van Allen, Dávid Szüts, Kent W Mouw, Zoltan Szallasi
Translational Cancer Genomics, Danish Cancer Society., Radiation oncology, Dana-Farber Cancer Institute., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center., Translational Cancer Genomics, Danish Cancer Society Research Center., Department of Radiation Oncology, Dana-Farber Cancer Institute., Boston Children's Hospital., Dana Farber Harvard Cancer Center., Semmelweis University., Department of Physics of Complex Systems, Eötvös Loránd University ELTE., Department of Oncology, Rigshospitalet., Radiation Oncology, Dana-Farber Cancer Institute., Department of Radiation Oncology, James Cancer Hospital, The Ohio State University., Medical Oncology, Dana-Farber Cancer Institute., Medical Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins., Hematology and Oncology, Fox Chase Cancer Center., Medicine, Memorial Sloan Kettering Cancer Center., Cancer Biology, Dana-Farber Cancer Institute., GU Oncology, Dana-Farber Cancer Institute., Novo Nordisk Foundation Center for Protein Research, University of Copenhagen., Institute of Enzymology, Research Centre for Natural Sciences., Department of Medical Oncology, Dana-Farber Cancer Institute., Radiation Oncology, Dana-Farber Cancer Institute/Brigham & Women's Hospital., Children's Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/33208343