LAUSR

ATM and ATR are central kinases in the cellular response to DNA damage and play a crucial role in maintaining genome integrity. Inactivation of ATM has been observed in multiple tumor types and pre-clinical studies suggest that inhibition of ATR is synthetic-lethal in ATM-deficient tumors. More than 10% of gastric cancers carry potentially deleterious mutations in ATM and patients with ATM-deficient gastric cancers could potentially benefit from ATR inhibitor-based therapy. This study focuses on establishing the critical parameters for clinical development of ATR inhibitors in treating gastric cancer. First, we tested the cytotoxic response to ATR inhibition of ATM-deficient and ATM-complemented derivative of human fibroblasts. Next, we utilized a panel of gastric cancer cell lines that represent the spectrum of ATM mutations and ATM expression levels to further confirm the correlation between reduced ATM activity and the cytotoxic effects of ATR inhibition. Third, we evaluated the effect of a series of missense and truncating mutations in ATM that were identified in The Cancer Genome Atlas (TCGA) project. Finally, we developed an immunohistochemistry (IHC) assay to assess the expression level of ATM in gastric tumor samples. Our results confirmed that ATM-deficient human fibroblasts were acutely sensitive to ATR inhibition compared to ATM-complemented cells. Acute sensitivity to ATR inhibition was also observed in gastric cancer cell lines that carry deleterious mutations in ATM and in those that express very low levels of ATM. Complementation experiments with mutant versions of the ATM ORF using ATM-deficient human fibroblasts identified deleterious mutations in ATM that sensitize to ATR inhibition. The IHC assay was applied to a cohort of 208 primary gastric cancers. ATM expression was undetectable in approximately 11% of the samples; an additional 26% expressed very low levels. Our findings suggest that ATR inhibition may elicit favorable responses in gastric cancer patients with tumors harboring deleterious ATM mutations or very low levels of ATM expression. Targeted exon-sequencing methods that are used widely combined with IHC for ATM may be useful for patient selection. Citation Format: Mu-Yan Cai, Hunter D. Reavis, Jie-Wei Chen, Chirag Ganesa, Bose Kochupurakkal, Geoffrey I. Shapiro, Alan D. D9Andrea. ATR inhibition for the treatment of ATM-deficient gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1620.