Background: Identification of synthetically lethal cellular targets and synergistic drug combinations are important in cancer chemo therapy as they help to overcome treatment resistance and increase efficacy. The Ataxia Telangiectasia Mutated (ATM) kinase is a nuclear protein that plays a major role in the initiation of DNA repair signalling and cell cycle check points during DNA damage. Although ATM was shown to be associated with poor prognosis in gastric cancer, its potential implication as a predictive biomarker for cancer chemotherapy remains unexplored. The present study evaluated ATM induced synthetic lethality and its role in sensitization of gastric cancer cells to PARP and TOP1 inhibitors, ABT-888 and CPT-11 respectively.
Methods: ATM expression in a panel of 10 gastric cancer cells were detected by immunohistochemistry and the IC50 against ABT-888 and CPT-11 was determined by MTS cell proliferation assay. The synergistic effect of ABT-888 and CPT-11 in gastric cancer cells was determined by cell cycle and DNA damage assays. ATM expression was knocked down using siRNA and its effect in P53 induced cell cycle regulation and apoptosis was determined by immunoblot analysis.
Results and Conclusion: ATM deficiency was found to be associated with enhanced sensitivity to ABT-888 and CPT-11 monotherapy, hence suggesting a mechanism of synthetic lethality. Cells with high ATM expression showed reduced sensitivity to monotherapy, however showed a higher synergistic effect towards ABT-888 and CPT-11 combinational therapy that predisposed cells to enhanced drug sensitivity. Furthermore, ATM expression was shown to play a major role in cellular homeostasis by regulating cell cycle progression and apoptosis in a P53 independent manner. The present study highlights the clinical utility of ATM expression as a predictive marker for sensitivity of gastric cancer cell to PARP and TOP1 inhibition and provides a deeper mechanistic insight into ATM dependent regulation of cellular processes.
Citation Format: Vinod Vijayasubhash, Shihui Tan, Fui Leng Yan, Natalia Liem, Wei Peng Yong. Atm expression predicts ABT-888 and CPT-11 sensitivity in gastric cancer cells by mediating p53 independent regulation of cell cycle and apoptosis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4937.