Abstract B08: MSH2 downregulation induces chemoresistance in bladder cancer

Abstract

Abstract Treatment of muscle-invasive bladder cancer has seen little improvement in three decades. The objective of this study is to identify genes and pathways that associate with cisplatin resistance in bladder cancer. A whole-genome, CRISPR-based screen was performed in the MGHU4 bladder cancer cell line treated with cisplatin to identify genes that mediate resistance to cisplatin. Targeted validation was performed in vitro in another bladder cancer cell line, 253J. MSH2 and MLH1 are prominent components of the mismatch repair. These are the top two genes that have the largest effect on cisplatin resistance according to our synthetic lethal screen. Bladder cancer cells with an MSH2 knockdown are resistant to cisplatin in vitro, in part due to a reduction in apoptosis. MSH2 was also investigated in a publicly available bladder cancer dataset containing 340 bladder cancer patients with treatment, protein, and survival information. Bladder cancer patients with low protein levels of MSH2 have poorer overall survival when treated with cisplatin- or carboplatin-based therapy. If confirmed in follow-up studies, MSH2 protein level may serve as a prospective biomarker of chemotherapy response in this cancer type. Note: This abstract was not presented at the conference. Citation Format: Andrew E. Goodspeed, Annie Jean, James C. Costello. MSH2 downregulation induces chemoresistance in bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B08.