P1.03-42 Angiotensin System Inhibitors Improve Survival in Stage IIIA NSCLC and Show Anti-Tumor Effect in Combination with Chemotherapy in a Model of NSCLC

Abstract

There is increasing interest in the renin-angiotensin system and its influence on tumor microenvironment. This study investigates the anti-tumor effect of angiotensin system inhibitors (ASI) on the multi-modality treatment of stage IIIA NSCLC and examines a potential mechanism in a murine model of lung cancer. We retrospectively reviewed the medical records of 125 patients at a single institution diagnosed with clinical stage IIIA NSCLC who underwent induction chemo-radiotherapy followed by surgery between 2009-2015. Overall survival was compared in patients on or off ASI's. To assess the antitumor efficacy and mechanism of ASI’s, cell culture models of lung cancer were treated with losartan or combination losartan+cisplatin and assessed cell survival. Mechanism was investigated with markers of epithelial-mesenchymal transition or surrogates of other signaling pathways (AKT, Stat3, PD-L1). Losartan was then tested in a murine model of lung cancer. ASI was associated with improved overall survival on multi-variate analysis of patients treated with multi-modality therapy for stage IIIA NSLC (p =0.047) [Figure 1A]. Losartan(≥0.5μM) significantly inhibited proliferation and migration of multiple human lung cancer cells, (H441, H358, H1299, SW1573) and a murine lung cancer adenocarcinoma, TC-1. The combination of Losartan and cisplatin significantly improved the cytotoxic effect of cisplatin in lung cancer cells in vitro (SW1573 p =0.020, TC-1 p =0.012) and reduced the tumor volume of (SW1573-Nude mice, p =0.045 [Figure 1B]; TC-1-C57BL/6 mice, G, p =0.001) in a murine flank tumor model as compared to single drug treatment. Combination treatment also significantly inhibited epithelial to mesenchymal transition and down-regulated the expression of AKT, Stat3, and PD-L1. ASI treatment influences survival in stage IIIA NSCLC. Losartan improves the anti-tumor effect of cytotoxic chemotherapy in lung cancer invitro and significantly reduces tumor burden in a murine lung cancer model. This study suggests a role for ASI therapy in the treatment of lung cancer.