Daniel L Menezes, Jenny Holt, Yan Tang, Jiajia Feng, Paul Barsanti, Yue Pan, Majid Ghoddusi, Wei Zhang, George Thomas, Jocelyn Holash, Emma Lees, Lorena Taricani

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.