Metastatic urothelial carcinoma of the bladder is generally incurable by current systemic therapy. Molecular characterization of bladder cancer (BLCa) has revealed multiple candidate driver genes for BLCa tumorigenesis. Epigenetic/chromatin modifiers have been shown to be frequently mutated in BLCa, with ARID1A mutations highly prevalent in nearly 20% of early and late stage tumors. EZH2 is a histone methyltransferase that acts as an oncogene. The data herein show that ARID1A deficient tumors, but not ARID1A wild-type tumors are sensitive to EZH2 inhibition. Specifically, EZH2 inhibitor-treated ARID1A deficient bladder cancer cells show significantly reduced cell viability, colony formation, and in vivo tumor growth relative to ARID1A-wild type bladder cancer cells. Thus, our study suggests that a specific subset of bladder cancer patients with ARID1A mutations can be therapeutically treated with pharmacologic inhibitors targeting EZH2.

中文翻译：

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ARID1A突变和缺陷型膀胱癌对EZH2药理抑制敏感

膀胱转移性尿路上皮癌通常可通过当前的全身疗法治愈。膀胱癌（BLCa）的分子表征揭示了BLCA肿瘤发生的多个候选驱动基因。已显示表观遗传/染色质修饰剂在BLCa中经常发生突变，其中ARID1A突变在近20％的早期和晚期肿瘤中高度流行。EZH2是一种组蛋白甲基转移酶，可作为致癌基因。本文中的数据显示ARID1A缺乏的肿瘤，但ARID1A野生型肿瘤对EZH2抑制敏感。具体而言，相对于ARID1A野生型膀胱癌细胞，EZH2抑制剂治疗的ARID1A缺陷膀胱癌细胞显示出明显降低的细胞活力，集落形成和体内肿瘤生长。从而，