Abstract A38: ATM inhibitor synergizes with glycolysis inhibition in ovarian cancer cells

Abstract

Abstract Epithelial ovarian cancer (EOC) is the deadliest gynecologic malignancy in the USA. While therapies such as inhibitors against poly (ADP-Ribose) polymerase (PARP) are emerging as the standard treatment for EOC patients, this strategy is limited to the subset of patients harboring particular genetic alterations in the DNA damage response pathway, making them homologous recombination (HR) deficient. Approximately 50% of EOC patients are HR proficient, which corresponds to PARP inhibitor resistance and worse patient survival. Therefore, novel therapies for this subset of patients are urgently needed. We found that the DDR gene ATM is upregulated in a subset of EOC patients, which is associated with worse progression-free survival. This suggests that targeting ATM may be beneficial for these EOC patients. Our previous publication demonstrated that inhibition of ATM alters cellular metabolism. Therefore, we aimed to explore ATM inhibitor-mediated metabolic vulnerabilities in EOC to develop them as novel therapeutic strategies. We found that inhibition of ATM increases glucose uptake but not lactate of multiple EOC cells using YSI Bioanalyzer and the fluorescent glucose analog 2NBDG by flow cytometry. Seahorse analysis further indicates that glucose is not being used for Warburg effect. Using an shRNA screen, we identified SLC2A11 and SLC2A12 as the transporters that mediate glucose uptake upon ATM inhibition. To determine whether the observed changes can be exploited for therapeutic benefit, we combined ATM inhibition with the known inhibitor of glycolysis, fenofibrate. We found that while neither ATM inhibition or fenofibrate alone had a robust effect on cell proliferation, the combination was synergistic. Mechanistically, we determined that the combination resulted in cellular senescence using SA-B-Gal assay and detected PML body by immunofluorescence. Using 53PB1 and gH2AX as DDR markers, we concluded that the combination causing synthetic lethal is DDR independent manner. In this study, we found that ATM-SLC2A11/12 axis mediating glucose uptake in EOC cells. Mechanistically understand the role of ATM beyond DDR. Together, our results suggest that metabolic changes induced by ATM inhibitors in EOC are a potential target for the treatment for EOC. Citation Format: Chi-Wei Chen, Erika S. Dahl, Kelly E. Leon, Raquel Buj, Katherine M. Aird. ATM inhibitor synergizes with glycolysis inhibition in ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A38.