期刊
MOLECULAR CANCER RESEARCH
卷 13, 期 1, 页码 120-129出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-14-0240
关键词
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Mechanisms to maintain genomic integrity are essential for cells to remain viable. Not surprisingly, disruption of key DNA damage response pathway factors, such as ataxia telangiectasia-mutated (ATM)/ataxia telangiectasia and RAD3-related (ATR) results in loss of genomic integrity. Here, a synthetic lethal siRNA-screening approach not only confirmed ATM but identified additional replication checkpoint proteins, when ablated, enhanced ATR inhibitor (ATRi) response in a high-content gamma-H2AX assay. Cancers with inactivating ATM mutations exhibit impaired DNA double-stranded break (DSB) repair and rely on compensatory repair pathways for survival. Therefore, impairing ATR activity may selectively sensitize cancer cells to killing. ATR inhibition in an ATM-deficient context results in phosphoryla-tion of DNA-dependent protein kinase catalytic subunits (DNA-PKcs) and leads to induction of gamma-H2AX. Using both in vitro and in vivo models, ATR inhibition enhanced efficacy in ATM loss-offunction mantle cell lymphoma (MCL) compared with ATM wild-type cancer cells. In summary, single-agent ATR inhibitors have therapeutic utility in the treatment of cancers, like MCL, in which ATM function has been lost. (C) 2014 AACR.
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