Mechanisms to maintain genomic integrity are essential for cells to remain viable. Not surprisingly, disruption of key DNA damage response (DDR) pathway factors, such as ataxia telangiectasia-mutated (ATM)/ATM- 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 g-H2AX assay. Cancers with inactivating ATM mutations exhibit impaired DNA double-stranded break repair (DSB) 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 g-H2AX. Using both in vitro and in vivo models, ATR inhibition enhanced efficacy in ATM loss-of-function mantle cell lymphoma (MCL) compared to 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 utilizes a complex and coordinated set of proteins to maintain genomic stability which could be further exploited.
- Received May 5, 2014.
- Revision received August 18, 2014.
- Accepted August 31, 2014.
- Copyright © 2014, American Association for Cancer Research.