Combined treatment with PI3K inhibitor BKM120 and PARP inhibitor olaparib is effective in inhibiting the gastric cancer cells with ARID1A deficiency

Abstract

Dual blockade of phosphoinositide 3-kinase (PI3K) and poly(ADP-ribose) polymerase (PARP) has been revealed to be an effective treatment strategy for breast, ovarian and prostate cancer. However, the efficacy of this combination for the treatment of gastric cancer, and potential predictive therapeutic biomarkers remain unclear. Recent evidence suggests that the deficiency of AT-rich interactive domain containing protein 1A (ARID1A), which is a crucial chromatin remodeling gene, sensitizes tumor cells to PI3K and PARP inhibitors. Herein, we evaluated the therapeutic role of the combined treatment of PI3K inhibitor BKM120 and PARP inhibitor olaparib on gastric cancer cells, and explored ARID1A as a predictive biomarker. The results demonstrated that combined treatment with PI3K and PARP inhibitors effectively inhibited proliferation detected by MTS and clonogenic assay, invasion and migration by Transwell assay, of gastric cancer cells with ARID1A deficiency. Mechanistically, dual blockade of PI3K and PARP in ARID1A-depleted gastric cancer cells significantly increased apoptosis detected by flow cytometry, and induced DNA damage by immunofluorescent staining. Taken together, these data suggest that the combined treatment with PI3K inhibitor BKM120 and PARP inhibitor olaparib may be a promising therapeutic regimen for the treatment of gastric cancer, and ARID1A deficiency could serve as a potential predictive therapeutic biomarker.