ARID1A mutation sensitizes most ovarian clear cell carcinomas to BET inhibitors.
ARID1A mutation sensitizes most ovarian clear cell carcinomas to BET inhibitors.
复制标题
ARID1A突变使大多数卵巢透明细胞癌对BET抑制剂敏感。
DOI：
10.1038/s41388-018-0300-6
复制
发表时间：
2018-08
期刊：
影响因子：
8
通讯作者：
Bernards R
中科院分区：
文献类型：
--
作者：
Berns K;Caumanns JJ;Hijmans EM;Gennissen AMC;Severson TM;Evers B;Wisman GBA;Jan Meersma G;Lieftink C;Beijersbergen RL;Itamochi H;van der Zee AGJ;de Jong S;Bernards R
目前对晚期卵巢透明细胞癌的治疗由于缺乏有效的全身治疗选择而受到严重阻碍，导致这些患者的前景不佳。测序研究表明，超过50%的卵巢透明细胞癌中ARID 1A发生突变。为了寻找靶向ARID 1A突变的卵巢透明细胞癌的合理方法，我们在一大组卵巢透明细胞癌细胞系中进行了以激酶组为中心的致死性筛选。使用迄今为止建立的最大的OCCC细胞系组，我们在这里表明，BRD 2抑制在ARID 1A突变的卵巢透明细胞癌细胞中主要是致命的。重要的是，BRD 2所属的BET（布罗莫结构域和额外末端结构域）蛋白家族的小分子抑制剂在体外和卵巢透明细胞癌异种移植物和患者来源的异种移植物模型中特异性抑制ARID 1A突变细胞系的增殖。BET抑制剂导致包括ARID 1B在内的多个SWI/SNF成员的表达减少，为观察到的与ARID 1A损失的致死相互作用提供了潜在的解释。我们的数据表明，BET抑制可能代表了一种新的治疗策略的一个子集的ARID 1A突变的卵巢透明细胞癌。
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.
登录
查看更多内容
影响因子：
8.8
作者：
Khursheed M;Kolla JN;Kotapalli V;Gupta N;Gowrishankar S;Uppin SG;Sastry RA;Koganti S;Sundaram C;Pollack JR;Bashyam MD
通讯作者：
Bashyam MD
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.0806213105
发表时间：
2008-11-25
影响因子：
11.1
作者：
Herold, Marco J.;van den Brandt, Jens;Reichardt, Holger M.
通讯作者：
Reichardt, Holger M.
影响因子：
50.5
作者：
Prat, J.
通讯作者：
Prat, J.
组织学类型对上皮卵巢，输卵管和腹膜癌的自由基原发性肿瘤后的手术结局和存活的作用。
影响因子：
8.8
作者：
Braicu, E-I;Sehouli, J.;Richter, R.;Pietzner, K.;Denkert, C.;Fotopoulou, C.
通讯作者：
Fotopoulou, C.