Current treatment for advanced stage ovarian clear cell cancer is severely hampered by a lack of effective systemic therapy options, leading to a poor outlook for these patients. Sequencing studies revealed that ARID1A is mutated in over 50% of ovarian clear cell carcinomas. To search for a rational approach to target ovarian clear cell cancers with ARID1A mutations, we performed kinome-centered lethality screens in a large panel of ovarian clear cell carcinoma cell lines. Using the largest OCCC cell line panel established to date, we show here that BRD2 inhibition is predominantly lethal in ARID1A mutated ovarian clear cell cancer cells. Importantly, small molecule inhibitors of the BET (bromodomain and extra terminal domain) family of proteins, to which BRD2 belongs, specifically inhibit proliferation of ARID1A mutated cell lines, both in vitro and in ovarian clear cell cancer xenografts and patient-derived xenograft models. BET inhibitors cause a reduction in the expression of multiple SWI/SNF members including ARID1B, providing a potential explanation for the observed lethal interaction with ARID1A loss. Our data indicate that BET inhibition may represent a novel treatment strategy for a subset of ARID1A mutated ovarian clear cell carcinomas.

中文翻译：

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ARID1A突变可使大多数卵巢透明细胞癌对BET抑制剂敏感。

缺乏有效的全身治疗选择严重阻碍了目前对晚期卵巢透明细胞癌的治疗，导致这些患者的前景不佳。测序研究表明，ARID1A在超过50％的卵巢透明细胞癌中发生了突变。为了寻找一种针对具有ARID1A突变的卵巢透明细胞癌的合理方法，我们在一大批卵巢透明细胞癌细胞系中进行了以基因组为中心的致死率筛选。使用迄今为止建立的最大的OCCC细胞系，我们在这里显示BRD2抑制主要在ARID1A突变的卵巢透明细胞癌细胞中具有致命性。重要的是，BRD2所属的BET（溴结构域和额外末端结构域）蛋白家族的小分子抑制剂可特异性抑制ARID1A突变的细胞系的增殖，无论是在体外还是在卵巢透明细胞癌异种移植和患者衍生的异种移植模型中。BET抑制剂导致包括ARID1B在内的多个SWI / SNF成员的表达减少，这为观察到的与ARID1A丧失的致命相互作用提供了可能的解释。我们的数据表明，BET抑制可能代表了一种针对ARID1A突变的卵巢透明细胞癌的子集的新型治疗策略。