Tumor genomic profiling has demonstrated that chromatin modifiers are frequently mutated in urothelial bladder cancers. The initial description of the mutational landscape of human bladder tumors indicated that 89% of cases had at least one alteration in histone-modifying genes and 64% had alterations in components of the SWI/SNF chromatin remodeling complex, suggesting that epigenetic dysregulation may play an important role in development and progression of bladder tumors. Among chromatin modifiers, ARID1A, a key component of the SWI/SNF remodeling complex, shows mutation rates of 25% in muscle-invasive bladder cancers. The chromatin modifier EZH2 functions in the suppression of gene expression. EZH2 is a histone lysine methyltransferase and the catalytic subunit of the PRC2 complex, which methylates histone H3 at lysine 27 (H3K27) to generate the transcriptionally repressive trimethylated modification state H3K27me3. EZH2 is frequently overexpressed in a wide variety of cancers, where it represses key tumor suppressors and genes involved in apoptosis and differentiation and, thus, often correlates with poor prognosis and survival. Given the role of EZH2 in cancer, we are currently developing the EZH2 inhibitor CPI-1205 in patients with castration-resistant prostate cancer. Recent publications have suggested that mutations in ARID1A create hypersensitive contexts for EZH2 inhibition in ovarian clear cell carcinomas. Given the high frequency of ARID1A mutations in bladder cancer, we were interested in whether a similar hypersensitive context exists for EZH2 inhibition in this indication. Long-term phenotypic growth assays in a panel of 21 bladder cancer cell lines treated with our second-generation EZH2 inhibitor CPI-0209 demonstrated preferential sensitivity in cell lines harboring ARID1A mutations. Sensitive cell lines showed increased subG1 populations compared to nonresponsive lines, indicating increased cell death in response to long-term EZH2 inhibition. Transcriptional profiling after CPI-0209 treatment in a panel of bladder cancer cell lines with and without ARID1A mutations showed widespread activation of EZH2 target gene expression, consistent with EZH2's transcriptionally repressive functions. These effects also translated to efficacy in vivo, where CPI-0209 treatment in bladder cell-line derived xenografts harboring ARID1A mutations led to dose-dependent tumor growth inhibition and tumor regression. Further, cotreatment of CPI-0209 with the chemotherapeutic agent cisplatin demonstrated combinatorial effects on cell viability in vitro and on in vivo tumor growth, suggesting EZH2 inhibition is also beneficial in the context of current chemotherapeutic agents in use for bladder cancers. These data support further investigation of CPI-0209 in clinical trials in bladder cancers with ARID1A mutations.
Citation Format: Patricia J. Keller, Rosana Meyer, Emily Greenwald, Xinwei Han, Andrew R. Conery, Jennifer A. Mertz, Patrick Trojer. Targeting epigenetic dysregulation in bladder cancer through inhibition of EZH2 [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 A18.