Abstract 2648: A novel dual inhibitor for AKT and EGFR signaling inhibits the growth of lung cancer cells

Abstract

Lung cancer is the leading cause of deaths worldwide due to cancer, of which non-small cell lung cancer is more common making up about 80 percent of lung cancer cases. Although early detection of lung cancer is feasible, targeted therapies importance are growing for advanced lung cancer. EGFR inhibitor is one of the potent options for non-small cell lung cancer (NSCLC), either alone or in combinations with chemotherapy drugs, erlotinib, gefitinib and afatinib; however the complete remission is not yet achieved. Hence, our goal is to dissect the role behind EGFR resistance in NSCLC. Our results suggested a concomitant activation of AKT which was also evident in EGFR expressed of NSCLC. So, we hypothesized that inhibiting both AKT as well as EGFR signaling, could be a promising strategy for treatment of lung cancer. Recently we identified a small molecule, 6-dimethyl, dihydro pyranone (6ddp), that inhibits both AKT (pAKTser473) and EGFR signaling in NSCLC, which resulted growth inhibition of A549 and H460 lung cancer cell lines. Interestingly, the IC50 concentrations were at 1.5nm and 0.3nm in both the lung cancer cell lines. Inhibition of both pro-survival signaling by a small molecule, activated induction of apoptosis by up regulating caspase mediated pro-apoptotic signaling (cleaved caspase) in NSCLC cells. Interestingly, the potent molecule inhibits epithelial-mesenchymal transition (EMT) in A549 and H460 cells by modulating the kinetics of E-Cadherin, β-Catenin expression. Currently, we are planning to validate these interesting findings in animal models, which is essential to translate into clinics. Citation Format: Arokya Mary Sashi Papu John, Murali Ankem, Chendil Damodaran. A novel dual inhibitor for AKT and EGFR signaling inhibits the growth of lung cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2648. doi:10.1158/1538-7445.AM2015-2648