Abstract
Background The response to first-line, platinum-based treatment of muscle-invasive bladder cancer has not improved in three decades.
Objective The objective of this study is to identify genes that predict cisplatin resistance in bladder cancer.
Design We performed a whole-genome, CRISPR-based screen in a bladder cancer cell line treated with cisplatin to identify genes that mediate response to cisplatin. Targeted validation was performed in vitro across two bladder cancer cell lines. The top gene candidate was validated in a publicly available bladder cancer dataset containing 340 bladder cancer patients with treatment, protein, and survival information.
Results and limitations The cisplatin resistance screen suggested the mismatch repair pathway through the loss of MSH2 and MLH1 contribute to cisplatin resistance. Bladder cancer cells depleted of MSH2 are resistant to cisplatin in vitro, in part due to a reduction in apoptosis. These cells maintain sensitivity to the cisplatin-analog, oxaliplatin. Bladder tumors with low protein levels of MSH2 have poorer overall survival when treated with cisplatin- or carboplatin-based therapy.
Conclusions We generated in vitro and clinical support that bladder cancer cell lines and tumors with low levels of MSH2 are more resistant to cisplatin-based therapy. Further studies are warranted to determine the ability of MSH2 protein levels to serve as a prospective biomarker of chemotherapy response in bladder cancer.
Patient summary We report the first evidence that the protein level of MSH2 may contribute to chemotherapy resistance observed in bladder cancer. MSH2 levels has the potential to serve as a biomarker of treatment response.
Footnotes
Financial support: This work is supported by the Boettcher Foundation (J.C.C.), T32GM007635 (A.G.), the Front Range Cancer Challenge (A.G.), and in part by the Genomics, Functional Genomics, and the Biostatistics & Bioinformatics Shared Resource of the University of Colorado Cancer Center (P30CA046934).
Conflict of interest disclosure statement: No potential conflicts of interest are disclosed.
