ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A.
ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A.
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DOI：
10.1038/ncomms13837
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发表时间：
2016-12-13
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
鉴定合成致死药物敏感性效应的遗传生物标志物为开发靶向癌症疗法提供了一种方法。ARID 1A中的突变代表了人类癌症中最常见的分子改变之一，但针对这些缺陷的治疗方法尚未在临床上可用。我们证明了ARID 1A的缺陷使肿瘤细胞对DNA损伤检查点激酶ATR的临床抑制剂在体外和体内都敏感。从机制上讲，ARID 1A缺陷导致拓扑异构酶2A和细胞周期缺陷，这导致对ATR检查点活性的依赖增加。在ARID 1A突变肿瘤细胞中，ATR的抑制触发过早的有丝分裂进入、基因组不稳定性和凋亡。本文提供的数据为评估ARID 1A缺陷作为单药ATR抑制剂反应的生物标志物提供了临床前和机制依据，并代表了靶向肿瘤细胞的新型合成致死方法。BAF SWI/SNF复合物亚基的突变在癌症中是常见的，但选择性治疗方法还不可用。在这里，作者证明了ARID 1A和其他亚基的缺陷以合成致死的方式使癌细胞对DNA检查点激酶抑制剂ATR敏感。
Identifying genetic biomarkers of synthetic lethal drug sensitivity effects provides one approach to the development of targeted cancer therapies. Mutations in ARID1A represent one of the most common molecular alterations in human cancer, but therapeutic approaches that target these defects are not yet clinically available. We demonstrate that defects in ARID1A sensitize tumour cells to clinical inhibitors of the DNA damage checkpoint kinase, ATR, both in vitro and in vivo. Mechanistically, ARID1A deficiency results in topoisomerase 2A and cell cycle defects, which cause an increased reliance on ATR checkpoint activity. In ARID1A mutant tumour cells, inhibition of ATR triggers premature mitotic entry, genomic instability and apoptosis. The data presented here provide the pre-clinical and mechanistic rationale for assessing ARID1A defects as a biomarker of single-agent ATR inhibitor response and represents a novel synthetic lethal approach to targeting tumour cells. Mutations in the BAF SWI/SNF complex subunits are frequent in cancers but selective therapeutic approaches are not available yet. Here, the authors demonstrate that defects of ARID1A and other subunits sensitizes cancer cells to the DNA checkpoint kinase inhibitor ATR in a synthetic lethal manner.
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影响因子：
16
作者：
Liu S;Shiotani B;Lahiri M;Maréchal A;Tse A;Leung CC;Glover JN;Yang XH;Zou L
通讯作者：
Zou L
哺乳动物SWI/SNF复合物的蛋白质组学和生物信息学分析确定了在人类恶性肿瘤中的广泛作用。
影响因子：
30.8
作者：
Kadoch, Cigall;Hargreaves, Diana C.;Hodges, Courtney;Elias, Laura;Ho, Lena;Ranish, Jeff;Crabtree, Gerald R.
通讯作者：
Crabtree, Gerald R.
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
11.4
作者：
Hohmann, Anja F.;Vakoc, Christopher R.
通讯作者：
Vakoc, Christopher R.
DOI：
10.1158/1078-0432.ccr-15-0479
发表时间：
2015-11-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Karnitz LM;Zou L
通讯作者：
Zou L