Recurrent somatic mutations in the BRG1/BRM-associated factor (BAF) chromatin remodeling complex subunit ARID1A occur frequently in advanced urothelial, endometrial, and ovarian clear cell carcinomas, creating an alternative chromatin state that may be exploited therapeutically. The histone methyltransferase EZH2 has been previously identified as targetable vulnerability in the context of ARID1A mutations. In this study, we describe the discovery of tulmimetostat, an orally available, clinical stage EZH2 inhibitor, and it elucidates the aspects of its application potential in ARID1A mutant tumors. Tulmimetostat administration achieved efficacy in multiple ARID1A mutant bladder, ovarian, and endometrial tumor models and improved cisplatin response in chemotherapy-resistant models. Consistent with its comprehensive and durable level of target coverage, tulmimetostat demonstrated greater efficacy than other PRC2-targeted inhibitors at comparable or lower exposures in a bladder cancer xenograft mouse model. Tulmimetostat mediated extensive changes in gene expression, in addition to a profound reduction in global H3K27me3 levels in tumors. Phase I clinical pharmacokinetic and pharmacodynamic data indicated that tulmimetostat exhibits durable exposure and profound target engagement. Importantly, a tulmimetostat controlled gene expression signature identified in whole blood from a cohort of 32 patients with cancer correlated with tulmimetostat exposure, representing a pharmacodynamic marker for the assessment of target coverage for PRC2-targeted agents in the clinic. Collectively, these data suggest that tulmimetostat has the potential to achieve clinical benefit in solid tumors as a monotherapy but also in combination with chemotherapeutic agents, and may be beneficial in various indications with recurrent ARID1A mutations. Significance: The EZH2 inhibitor tulmimetostat achieves comprehensive target inhibition in ARID1A mutant solid tumor models and cancer patients that can be assessed with a pharmacodynamic gene signature in peripheral blood.

中文翻译：

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EZH2 抑制剂 Tulmimetostat 的全面靶点参与可靶向 ARID1A 突变癌症。


BRG1/BRM 相关因子 (BAF) 染色质重塑复合物亚基 ARID1A 中的反复体细胞突变经常发生在晚期尿路上皮癌、子宫内膜癌和卵巢透明细胞癌中，从而产生可用于治疗的替代染色质状态。组蛋白甲基转移酶 EZH2 先前已被确定为 ARID1A 突变背景下的目标脆弱性。在这项研究中，我们描述了 tulmimetostat（一种口服的临床阶段 EZH2 抑制剂）的发现，并阐明了其在 ARID1A 突变肿瘤中的应用潜力。 Tulmimetostat 给药在多种 ARID1A 突变膀胱、卵巢和子宫内膜肿瘤模型中取得了疗效，并改善了化疗耐药模型中的顺铂反应。与其全面且持久的靶点覆盖水平相一致，在膀胱癌异种移植小鼠模型中，在相当或较低的暴露量下，tulmimetostat 表现出比其他 PRC2 靶向抑制剂更高的疗效。 Tulmimetostat 除了显着降低肿瘤中整体 H3K27me3 水平外，还介导基因表达的广泛变化。 I 期临床药代动力学和药效学数据表明，tulmimetostat 表现出持久的暴露和深刻的靶点参与。重要的是，在 32 名癌症患者的全血中发现了与妥米司他暴露相关的妥米司他控制的基因表达特征，代表了临床中用于评估 PRC2 靶向药物的靶点覆盖率的药效学标志物。 总的来说，这些数据表明，tulmimetostat 作为单一疗法有可能在实体瘤中实现临床获益，也可以与化疗药物联合使用，并且可能对复发性 ARID1A 突变的各种适应症有益。意义：EZH2 抑制剂 tulmimetostat 在 ARID1A 突变实体瘤模型和癌症患者中实现了全面的目标抑制，可以通过外周血中的药效基因特征进行评估。