Fanconi anemia pathway-deficient tumor cells are hypersensitive to inhibition of ataxia telangiectasia mutated
Fanconi anemia pathway-deficient tumor cells are hypersensitive to inhibition of ataxia telangiectasia mutated
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DOI：
10.1172/jci31245
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发表时间：
2007-05-01
影响因子：
15.9
通讯作者：
D'Andrea, Alan D.
中科院分区：
文献类型：
--
作者：
Kennedy, Richard D.;Chen, Clark C.;D'Andrea, Alan D.
范可尼贫血（Fanconi anemia， FA）通路维持复制细胞的基因组稳定性。零星见于乳腺、卵巢、胰腺和血液系统。肿瘤缺乏FA通路功能，导致对dna损伤剂敏感。这些肿瘤中的FA通路功能障碍可能导致对可作为治疗策略的替代DNA修复通路的过度依赖。我们使用高通量siRNA筛选方法鉴定出失调性毛细血管扩张突变（ATM）是FA通路缺陷的人成纤维细胞的关键激酶。观察到缺乏FA通路的人成纤维细胞和小鼠胚胎成纤维细胞具有组成性ATM激活，并且发现fang (-/-) ATM（-/-）小鼠无法存活。在FA通路缺陷的细胞中，ATM功能的丧失导致DNA断裂、细胞周期阻滞和细胞凋亡。此外，Fanconi贫血互补组G- (FANCG-)和fancc缺陷胰腺肿瘤系对ATM抑制剂KU-55933比等基因校正系更敏感。这些数据表明，ATM和FA基因在维持基因组完整性和细胞活力方面发挥平行和代偿作用。药物抑制ATM可能在治疗FA通路缺陷的人类癌症中起作用。
The Fanconi anemia (FA) pathway maintains genomic stability in replicating cells. Some sporadic breast, ovarian, pancreatic, and hematological. tumors are deficient in FA pathway function, resulting in sensitivity to DNA-damaging agents. FA pathway dysfunction in these tumors may result in hyperdependence on alternative DNA repair pathways that could be targeted as a treatment strategy. We used a high-throughput siRNA screening approach that identified ataxia telangiectasia mutated (ATM) as a critical kinase for FA pathway-deficient human fibroblasts. Human fibroblasts and murine embryonic fibroblasts deficient for the FA pathway were observed to have constitutive ATM activation and Fancg(-/-)Atm(-/-) mice were found to be nonviable. Abrogation of ATM function in FA pathway-deficient cells resulted in DNA breakage, cell cycle arrest, and apoptotic cell death. Moreover, Fanconi anemia complementation group G- (FANCG-) and FANCC-deficient pancreatic tumor lines were more sensitive to the ATM inhibitor KU-55933 than isogenic corrected lines. These data suggest that ATM and FA genes function in parallel and compensatory roles to maintain genomic integrity and cell viability. Pharmaceutical inhibition of ATM may have a role in the treatment of FA pathway-deficient human cancers.