Abstract IA23: Using PARP inhibitors to target ATM-deficient cancers

Abstract

Abstract The Ataxia-Telangiectasia Mutated (ATM) serine/threonine protein kinase plays an important role in orchestrating the cellular response to DNA double strand breaks (DSBs). Germline loss of ATM function results in Ataxia-Telangiectasia (A-T), a devastating childhood syndrome characterized by progressive loss of neuromuscular control, immune deficiency and cancer predisposition. ATM is also deleted in a large proportion of human mantle cell lymphoma (MCL) and other lymphomas and recent studies have revealed that ATM is altered in many sporadic cancers including lung, colorectal, breast and prostate cancer. We previously showed that MCL and gastric cancer cell lines with deletion or mutation of ATM are sensitive to the poly-ADP-ribose polymerase (PARP) inhibitor, olaparib and that loss of TP53 enhances olaparib sensitivity (Williamson et al Molecular Cancer Therapeutics, 2010, 9:347-57; Williamson et al, EMBO Molecular Medicine, 2012, 4, 515-527; Kubota et al, Cell Cycle 2014, 13: 2129-37). Here we show that lung and colorectal cancers with mutation or loss of ATM are similarly sensitive to olaparib. The potential for use of PARP and ATM inhibitors in the treatment of ATM deficient malignancies will be explored. Citation Format: Susan P. Lees-Miller. Using PARP inhibitors to target ATM-deficient cancers [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA23.