Xenograft of bladder cancer cell line HT1376 were treated with or without EZH2 inhibitors before subject to RNA-seq

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. Xenograft of bladder cancer cell line HT1376 were treated with or without EZH2 inhibitors before subject to RNA-seq.

晚期膀胱癌仍是临床治疗的棘手难题，对于绝大多数患者而言，当前的标准治疗方案最终往往难以奏效。该类肿瘤常携带BAF复合体亚基（BAF complex subunit）ARID1A的突变，已有研究表明这类突变可使多种肿瘤类型对EZH2抑制产生敏感性。本研究报道了CPI-0209的研发历程——这是一款同类最优、可口服的EZH2抑制剂。我们证实，携带ARID1A功能丧失（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，在化疗耐药模型中，其疗效亦优于顺铂（cisplatin），且可提升肿瘤应答水平。上述研究结果为晚期尿路上皮癌（urothelial carcinoma）患者开辟了全新的治疗机遇。本研究将膀胱癌细胞系HT1376的异种移植瘤模型分别施以EZH2抑制剂处理与空白对照，随后进行RNA测序（RNA-seq）。