Deciphering the Role of EZH2 Inhibition in Epigenetic Regulation of Bladder Cancer

Chromatin modifiers are often mutated in urothelial bladder cancers, with histone-modifying genes and the SWI/SNF complex showing high mutation rates, indicating a significant role in tumor development. The ARID1A gene, part of the SWI/SNF complex, is mutated in 25% of muscle-invasive cases. EZH2, a histone lysine methyltransferase, is overexpressed in various cancers, leading to repression of tumor suppressors and genes linked to apoptosis and differentiation, often associated with poor outcomes.

The development of the EZH2 inhibitor CPI-1205 is underway for castration-resistant prostate cancer. Studies have indicated that ARID1A mutations may make ovarian clear cell carcinomas more responsive to EZH2 inhibition. To explore this possibility in bladder cancer, a second-generation EZH2 inhibitor, CPI-0209, was tested on 21 bladder cancer cell lines. Cell lines with ARID1A mutations showed increased sensitivity to CPI-0209, with enhanced cell death and activation of EZH2 target genes.

In vivo studies with CPI-0209 on bladder cancer xenografts with ARID1A mutations resulted in tumor growth inhibition and regression. Additionally, the combination of CPI-0209 with cisplatin displayed synergistic effects on cell viability and tumor growth, suggesting that EZH2 inhibition could be beneficial alongside current chemotherapy for bladder cancer. These findings encourage further clinical trials of CPI-0209 in bladder cancers with ARID1A mutations.

Reference: Keller PJ, Meyer R, Greenwald E, et al. Targeting epigenetic dysregulation in bladder cancer through inhibition of EZH2 [abstract]. Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Clin Cancer Res 2020;26(15_Suppl):Abstract nr A18.