Epigenomic change of ARDI1A mutant bladder cancer cell line treated with CPI-0209 or induced ARID1A expression

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. HT1376-TetON control cells and a clonal HT1376-TetON-ARID1A cell line were induced with 50 ng/ml doxycycline for 24 hours and then treated for 4 days with DMSO or 250 nM CPI-0209.

晚期膀胱癌仍是临床难治性癌种，对于绝大多数患者而言，当前标准治疗最终往往难以奏效。此类肿瘤常携带BAF复合物亚基ARID1A（BAF complex subunit ARID1A）突变，已有研究证实该突变可使多种肿瘤类型对EZH2抑制（EZH2 inhibition）产生敏感性。本研究中我们成功开发出同类最优的口服EZH2抑制剂CPI-0209。我们证实，携带ARID1A功能缺失（loss of function (LOF)）突变的膀胱癌突变细胞系对EZH2抑制具有优先敏感性。CPI-0209单药治疗不仅可在ARID1A突变模型中引发显著的单药应答，其疗效还优于顺铂，且可改善化疗耐药模型的应答效果。上述研究结果为晚期尿路上皮癌患者带来了全新的治疗机遇。将HT1376-TetON对照细胞与单克隆HT1376-TetON-ARID1A细胞系用50 ng/ml多西环素（doxycycline）诱导24小时，随后分别用二甲基亚砜（DMSO）或250 nM CPI-0209处理4天。