<i>ERCC2</i> Helicase Domain Mutations Confer Nucleotide Excision Repair Deficiency and Drive Cisplatin Sensitivity in Muscle-Invasive Bladder Cancer.

Abstract

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 <i>ERCC2</i> as a biomarker predictive of response to cisplatin in MIBC. Somatic missense mutations in <i>ERCC2</i> are associated with improved response to cisplatin-based chemotherapy; however, clinically identified <i>ERCC2</i> mutations are distributed throughout the gene, and the impact of individual <i>ERCC2</i> variants on NER capacity and cisplatin sensitivity is unknown. We developed a microscopy-based NER assay to profile <i>ERCC2</i> mutations observed retrospectively in prior studies and prospectively within the context of an institution-wide tumor profiling initiative. In addition, we created the first <i>ERCC2</i>-deficient bladder cancer preclinical model for studying the impact of <i>ERCC2</i> loss of function. We used our functional assay to test the NER capacity of clinically observed <i>ERCC2</i> mutations and found that most <i>ERCC2</i> helicase domain mutations cannot support NER. Furthermore, we show that introducing an <i>ERCC2</i> 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 <i>ERCC2</i> mutations in driving cisplatin response, define the functional landscape of <i>ERCC2</i> mutations in bladder cancer, and provide an opportunity to apply combined genomic and functional approaches to prospectively guide therapy decisions in bladder cancer.<i>See related commentary by Grivas, p. 907</i>.