ERCC2 Helicase Domain Mutations Confer Nucleotide Excision Repair Deficiency and Drive Cisplatin Sensitivity in Muscle-Invasive Bladder Cancer

• Published in: Clinical cancer research Vol. 25; no. 3; pp. 977 - 988
• Main Authors: Li, Qiang, Damish, Alexis W, Frazier, Zoë, Liu, David, Reznichenko, Elizaveta, Kamburov, Atanas, Bell, Andrew, Zhao, Huiyong, Jordan, Emmet J, Gao, S Paul, Ma, Jennifer, Abbosh, Philip H, Bellmunt, Joaquim, Plimack, Elizabeth R, Lazaro, Jean-Bernard, Solit, David B, Bajorin, Dean, Rosenberg, Jonathan E, D'Andrea, Alan D, Riaz, Nadeem, Van Allen, Eliezer M, Iyer, Gopa, Mouw, Kent W
• Format: Journal Article
• Language: English
• Published: United States 01.02.2019
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cell Line; Cell Line, Tumor; Cisplatin - administration & dosage; Cohort Studies; DNA Repair - genetics; Female; Humans; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Muscles - pathology; Mutation, Missense; Neoplasm Invasiveness; Survival Analysis; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - pathology; Xenograft Model Antitumor Assays; Xeroderma Pigmentosum Group D Protein - genetics
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-1001

DNA-damaging agents comprise the backbone of systemic treatment for many tumor types; however, few reliable predictive biomarkers are available to guide use of these agents. In muscle-invasive bladder cancer (MIBC), cisplatin-based chemotherapy improves survival, yet response varies widely among patients. Here, we sought to define the role of the nucleotide excision repair (NER) gene as a biomarker predictive of response to cisplatin in MIBC. Somatic missense mutations in are associated with improved response to cisplatin-based chemotherapy; however, clinically identified mutations are distributed throughout the gene, and the impact of individual variants on NER capacity and cisplatin sensitivity is unknown. We developed a microscopy-based NER assay to profile mutations observed retrospectively in prior studies and prospectively within the context of an institution-wide tumor profiling initiative. In addition, we created the first -deficient bladder cancer preclinical model for studying the impact of loss of function. We used our functional assay to test the NER capacity of clinically observed mutations and found that most helicase domain mutations cannot support NER. Furthermore, we show that introducing an mutation into a bladder cancer cell line abrogates NER activity and is sufficient to drive cisplatin sensitivity in an orthotopic xenograft model. Our data support a direct role for mutations in driving cisplatin response, define the functional landscape of mutations in bladder cancer, and provide an opportunity to apply combined genomic and functional approaches to prospectively guide therapy decisions in bladder cancer. .