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Project description:Comprehensive target engagement by EZH2 inhibitor CPI-0209 allows for preferential targeting of ARID1A mutant urothelial carcinoma
| PRJNA736424 | ENA
Project description:Bladder cancer therapy relies on aggressive treatments highlighting the need for new, targeted therapies with reduced side effects. SWI/SNF complexes are mutated in ~20% across human cancers and dependency of SWI/SNF-deficient tumors on EZH2 has been uncovered recently. To systematically dissect the frequency of genetic alterations in SWI/SNF complexes potentially contributing to their inactivation, mutations and copy number variations in 25 SWI/SNF subunit genes were analyzed making use of publicly available sequencing data for 408 muscle-invasive bladder carcinoma samples. ARID1A truncating mutations were identified as the by far most common alterations of SWI/SNF complexes in urothelial bladder cancer. As current ARID1A protein expression data in bladder cancer are inconsistent and incomplete we examined if the frequency of truncating ARID1A mutations translates into a similar frequency of cases showing ARID1A protein loss. We applied a validated ARID1A antibody conducting a comprehensive immunohistochemistry-based expression analysis in urothelial bladder cancer (n = 362) including carcinoma in situ (CIS) cases. While observing increased median ARID1A protein levels in all carcinoma subgroups compared to normal urothelial controls (n = 21), the percentage of cases showing ARID1A protein loss was positively correlated with increasing stage and grade culminating in a rate of 14.1% in muscle-invasive disease. ARID1A-depletion did neither increase EZH2 protein or trimethylated H3K27 levels in vitro nor did ARID1A expression correlate with EZH2 or H3K27me3 amounts in human bladder carcinomas. Importantly, ARID1A-deficiency was neither associated with enhanced sensitivity towards inhibition of EZH2 enzymatic activity nor depletion of EZH2 protein. In summary, ARID1A truncating mutations, potentially translating into ARID1A protein loss in a subset of high-grade bladder cancers, are the most common SWI/SNF genetic alterations in bladder cancer. Our data do not support ARID1A-deficiency as predictive biomarker for EZH2-inhibitor treatment response in bladder cancer underlining the need for future bladder cancer-specific, drug screens for successfull discovery of ARID1A-deficiency-based targeted drugs.
| S-EPMC6107234 | biostudies-literature
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.
2024-06-26 | GSE176358 | GEO
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.
2024-06-26 | GSE176477 | GEO
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.
2024-06-26 | GSE176490 | GEO
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.
2024-05-31 | GSE264383 | GEO
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.
2024-06-26 | GSE176486 | GEO
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.
2024-06-26 | GSE176362 | GEO
Project description:The components of the Switch/Sucrose non-fermentable (SWI/SNF) complex are mutated in approximately 20% of human cancers. The A/T-rich interacting domain 1A (ARID1A) subunit has one of the highest mutation rates. Most notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas (OCCCs). We reported that inhibition of enhancer of zeste homology 2 (EZH2) is synthetically lethal in ARID1A-mutated OCCC.
| S-EPMC4845188 | biostudies-other
Project description:The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K-AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations.
| S-EPMC4352133 | biostudies-literature