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Börcsök J , Sztupinszki Z , Bekele R , Gao SP , Diossy M , Samant AS , Dillon KM , Tisza V , Spisák S , Rusz O , Csabai I , Pappot H , Frazier ZJ , Konieczkowski DJ , Liu D , Vasani N , Rodrigues JA , Solit DB , Hoffman-Censits JH , Plimack ER , Rosenberg JE , Lazaro JB , Taplin ME , Iyer G , Brunak S , Lozsa R , Van Allen EM , Szüts D , Mouw KW , Szallasi Z
Identification of a synthetic lethal relationship between nucleotide excision repair (NER) deficiency and irofulven sensitivity in urothelial cancer
Clin Cancer Res. 2021 Nov 18;27(7) :2011-2022
PMID: 33208343    PMCID: PMC8026514    URL: https://www.ncbi.nlm.nih.gov/pubmed/33208343
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PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.
Börcsök, Judit Orcid: 0000-0002-3290-3971 Sztupinszki, Zsofia Orcid: 0000-0002-8691-4086 Bekele, Raie Gao, Sizhi P Diossy, Miklos Orcid: 0000-0003-0308-6615 Samant, Amruta S Dillon, Kasia M Tisza, Viktoria Spisák, Sándor Rusz, Orsolya Csabai, Istvan Orcid: 0000-0001-9232-9898 Pappot, Helle Orcid: 0000-0002-3570-5372 Frazier, Zoe J Konieczkowski, David J Liu, David Orcid: 0000-0003-0346-5033 Vasani, Naresh Rodrigues, James A Solit, David B Hoffman-Censits, Jean H Plimack, Elizabeth R Rosenberg, Jonathan E Lazaro, Jean-Bernard Taplin, Mary-Ellen Iyer, Gopa Brunak, Søren Lozsa, Rita Van Allen, Eliezer M Szüts, Dávid Mouw, Kent W Szallasi, Zoltan Orcid: 0000-0001-5395-7509 Journal Article United States Clin Cancer Res. 2020 Nov 18:clincanres.3316.2020. doi: 10.1158/1078-0432.CCR-20-3316.