Abstract 1694: Combination of Indolizino[6,7-b]indole and Gefitinib synergistically suppresses the growth of EGFR-mutant NSCLC cells

Abstract

Abstract We have previously revealed that indolizino[6,7-b]indoles are effective antitumor agents against a variety of cancer cells. Indolizino[6,7-b]indoles were shown to induce DNA crosslinks and inhibit the enzymatic activities of topoisomerase I and II. Our recent results demonstrated that the derivatives of indolizino[6,7-b]indoles potently suppressed the cell growth of several non-small cell lung cancer (NSCLC) cells, including H460, PC9, PC9/gef B4, and H1975 cells in in vitro and in vivo systems. We also showed that BO-1978, one of indolizino[6,7-b]indole derivatives, completely suppressed the growth of CL1-5/GFP-Luciferase and PC9/gef B4-Luciferase cells in orthotopic lung cancer models. These results implicated that indolizino[6,7-b]indoles are potential candidate agents against NSCLC. EGFR mutations are frequently occurred in NSCLC. Although targeted agents such as Gefitinib is effectively suppression the growth of NSCLC with EGFR mutations, the resistance to Gefitinib is quickly developed and causes the failure of targeted treatments. Since the combination of targeted agents and cytotoxic drugs is one of strategies to overcome the problem encountered by targeted therapy, we further explore the therapeutic potential of combination of BO-1978 and Gefitinib against EGFR-mutant NSCLC. Our results showed that the combination treatment of PC9 and PC9/gef B4 cells with BO-1978 and Gefitinib resulted in synergistic induction of apoptosis and suppression of cell growth in cultured cells. We also confirmed the therapeutic efficacy of combined treatment of PC9 and PC9/gef B4 cells with BO-1978 and Gefitinib in xenografted tumor models. Since we did not observe severe body weight loss in mice received the combination treatment of BO-1978 and Gefitinib, our present studies apparently support that BO-1978 and its combination with Gefitinib is highly prospective as therapeutic agents against EGFR-mutant NSCLC. Citation Format: Chi-Wei Chen, Satishkumar Tala, Tsann-Long Su, Te-Chang Lee. Combination of Indolizino[6,7-b]indole and Gefitinib synergistically suppresses the growth of EGFR-mutant NSCLC cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1694. doi:10.1158/1538-7445.AM2014-1694