Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of ARID1A Mutant Cancers
Recurrent somatic mutations in the BRG1/BRM-associated factor (BAF) chromatin remodeling complex subunit ARID1A are common in advanced urothelial, endometrial, and ovarian clear cell carcinomas. These mutations create an alternative chromatin state that presents a therapeutic opportunity. The histone methyltransferase EZH2 has previously been identified as a targetable vulnerability in the context of ARID1A mutations. In this study, we report the discovery of tulmimetostat, an orally available, clinical-stage EZH2 inhibitor, and explore its potential applications in ARID1A mutant tumors. Tulmimetostat showed efficacy in multiple ARID1A mutant bladder, ovarian, and endometrial tumor models and enhanced the response to cisplatin in chemotherapy-resistant models. With its comprehensive and durable target coverage, tulmimetostat demonstrated superior efficacy compared to other PRC2-targeted inhibitors at similar or lower doses in a bladder cancer xenograft mouse model. Tulmimetostat induced extensive changes in gene expression and significantly reduced global H3K27me3 levels in tumors. Phase I clinical pharmacokinetic and pharmacodynamic data revealed that tulmimetostat maintains durable exposure and robust target engagement. Notably, a tulmimetostat-controlled gene expression signature identified in whole blood from a cohort of 32 cancer patients correlated with tulmimetostat exposure, serving as a pharmacodynamic marker for assessing target coverage of PRC2-targeted agents in clinical settings. These findings suggest that tulmimetostat could provide clinical benefits as a monotherapy and in combination with chemotherapeutic agents, particularly in tumors with recurrent ARID1A mutations. Significance: The EZH2 inhibitor tulmimetostat achieves comprehensive target inhibition in ARID1A mutant solid tumor models and in cancer patients, which can be assessed through a pharmacodynamic gene signature in peripheral blood.