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Epigenomic profile of bladder cancer cell line HT1376 treated with CPI-0209

ABSTRACT: Advanced bladder cancer remains a difficult cancer to treat, and for the majority of patients, current standard treatments ultimately prove ineffective. These tumors frequently harbor mutations in the BAF complex subunit ARID1A, which has been reported to confer sensitivity to EZH2 inhibition in several tumor types. Here we describe the generation of CPI-0209, a best-in-class, orally available EZH2 inhibitor. We show that mutant bladder cancer lines harboring ARID1A loss of function (LOF) mutations are preferentially sensitive to inhibition of EZH2. Treatment with CPI-0209 not only elicits a significant monotherapeutic response in ARID1A mutant models, it also outperforms cisplatin and improves response in chemo-resistant models. These findings shine light on new therapeutic opportunities for patients with advanced urothelial carcinoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE176486 | GEO | 2024/06/26

REPOSITORIES: GEO

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Study of CPI-0209 in patients with advanced tumors.

Project description:Advanced bladder cancer remains a difficult cancer to treat, and for the majority of patients, current standard treatments ultimately prove ineffective. These tumors frequently harbor mutations in the BAF complex subunit ARID1A, which has been reported to confer sensitivity to EZH2 inhibition in several tumor types. Here we describe the generation of CPI-0209, a best-in-class, orally available EZH2 inhibitor. We show that mutant bladder cancer lines harboring ARID1A loss of function (LOF) mutations are preferentially sensitive to inhibition of EZH2. Treatment with CPI-0209 not only elicits a significant monotherapeutic response in ARID1A mutant models, it also outperforms cisplatin and improves response in chemo-resistant models. These findings shine light on new therapeutic opportunities for patients with advanced urothelial carcinoma.

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Project description:Recurrent mutations in ARID1A occur frequently in advanced urothelial carcinoma, endometrial cancers and ovarian clear cell carcinoma, and may create an alternative chromatin state that can be exploited therapeutically. Previously, the histone methyltransferase EZH2 was identified as a targetable vulnerability in the context of ARID1A mutations. Here we describe the discovery of tulmimetostat (CPI-0209), a novel, orally available, clinical stage EZH2 inhibitor with remarkably long residence time and elucidate aspects of its application potential in ARID1A mutant tumors. Tulmimetostat administration as a single agent achieves in vivo efficacy in multiple ARID1A mutant bladder, ovarian, and endometrial tumor models and improves cisplatin response in chemotherapy-resistant models. Consistent with its potency and the comprehensive and durable level of target coverage, tulmimetostat demonstrates greater efficacy than other PRC2-targeted inhibitors at comparable or lower exposures in a bladder cancer xenograft mouse model due to greater changes in gene expression and a profound reduction of H3K27me3 levels in the tumors. Importantly, we report the identification of a tulmimetostat controlled gene expression signature in whole blood from a cohort of 32 cancer patients, whereby the number of genes altered in expression as well as the magnitude of expression changes exquisitely correlate with tulmimetostat exposure, thus representing a novel pharmacodynamic marker for the assessment of target coverage for PRC2-targeted agents in the clinic. Collectively, our data suggest tulmimetostat may unlock the full potential of EZH2 inhibition as a cancer therapeutic mechanism with potential applications in hematologic malignancies and in solid tumors, including in an ARID1A mutant setting.

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Project description:ARID1A, a subunit of SWI/SNF chromatin remodeling complex. SWI/SNF complex can regulate expression of genes involved in vital biological processes such as cell cycle, DNA damage repair and development. ARID1A is known to have high mutation rate in human cancers including bladder cancer, leading to its loss of function. Publicly available whole exome sequencing data for muscle invasive and non-muscle invasive bladder cancers, show fraction of tumors with truncated ARID1A. Thus identifying therapeutic strategies for ARID1A mutant cancers is of high importance. EZH2, a histone methyltransferase is known to over-express and play pivotal role in aggressive bladder cancer. Our preliminary studies show that treatment of EZH2 inhibitor (GSK126) on ARID1A mutant bladder cancer cells significantly reduced cancer cell viability, invasion and colony formation relative to wild type ARID1A containing cells. Here, we performed microarray experiments to assess the effect of EZH2 inhibitor on global transcriptome of both ARID1A mutant and wild type bladder cancer cell line.

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Targeting EZH2 methyltransferase activity in ARID1A mutated cells as a synthetic lethal therapeutic strategy

Project description:ARID1A, an epigentic modifier, is often mutated in ovarian clear cell carcinoma (OCCC). In addition, EZH2 is frequently upregulated in OCCC. Inhibtion of EZH2 with an inhibitor (GSK126) selectively inhibits ARID1A-mutated cells. This study was designed to understand changes in gene expression profiles following EZH2 inhibition or ARID1A restoration. Chromatin remodelers such as ARID1A are frequently mutated in a broad array of cancers. However, targeted cancer therapy based on ARID1A mutation status has not been described. Intriguingly, ARID1A mutated cancers typically lack genomic instability, suggesting significant involvement of epigenetic mechanisms. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A mutated cells. Remarkably, ARID1A mutation status correlated with response to EZH2 inhibitor. Genome-wide profiling revealed antagonistic roles of ARID1A and EZH2 in gene regulation. Further, we identified PIK3IP1 as a direct ARID1A/EZH2 target gene whose upregulation contributes to the observed synthetic lethality in the EZH2 inhibitor treated ARID1A mutated cells. Significantly, EZH2 inhibitor caused the regression of established ARID1A mutated tumors in vivo. Together, this data demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. They indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for ARID1A mutated cancers.

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