PT  - JOURNAL ARTICLE
AU  - Menezes, Daniel L.
AU  - Holt, Jenny
AU  - Tang, Yan
AU  - Feng, Jiajia
AU  - Barsanti, Paul
AU  - Pan, Yue
AU  - Ghoddusi, Majid
AU  - Zhang, Wei
AU  - Thomas, George
AU  - Holash, Jocelyn
AU  - Lees, Emma
AU  - Taricani, Lorena
TI  - A Synthetic Lethal Screen Reveals Enhanced Sensitivity to ATR Inhibitor Treatment in Mantle Cell Lymphoma with ATM Loss-of-Function
AID  - 10.1158/1541-7786.MCR-14-0240
DP  - 2015 Jan 01
TA  - Molecular Cancer Research
PG  - 120--129
VI  - 13
IP  - 1
4099  - http://mcr.aacrjournals.org/content/13/1/120.short
4100  - http://mcr.aacrjournals.org/content/13/1/120.full
SO  - Mol Cancer Res2015 Jan 01; 13
AB  - 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 γ-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 phosphorylation of DNA-dependent protein kinase catalytic subunits (DNA-PKcs) and leads to induction of γ-H2AX. Using both in vitro and in vivo models, ATR inhibition enhanced efficacy in ATM loss-of-function 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. Implications: These data suggest that single-agent ATR inhibitors have therapeutic utility and that ATR uses a complex and coordinated set of proteins to maintain genomic stability that could be further exploited. Mol Cancer Res; 13(1); 120–9. ©2014 AACR.This article is featured in Highlights of This Issue, p. 1