Abstract 3764: SC-1, a sorafenib derivative, induces apoptosis in epidermal growth factor receptor wild type non-small cell lung cancer through the inhibition of signal transducers and activators of transcription 3

Abstract

Abstract Background: Lung cancer is the leading cause of cancer-related death worldwide, but currently there are no available target therapies for EGFR wild type NSCLC patients. Sorafenib, a multiple kinase inhibitors, shows therapeutic effects in renal carcinoma (RCC) and hepatocellular carcinoma (HCC). Our data shows that the inhibition of signal transducers and activators of transcription 3 (STAT3), a transcription factor involving in cell proliferation and survival, represents a major mechanism whereby sorafenib induces apoptosis in HCC cells (Clin Cancer Res 2010). Therefore, we design and synthesize a sorafenib derivative, SC-1, which is devoid of kinase activity (J Hepatol 2011). SC-1 shows higher potency in inducing apoptosis than sorafenib. Here, we tested efficacy of SC-1 to EGFR wild type NSCLC and examined the drug mechanism. Methods: EGFR wild type NSCLC cell lines, A549 H292 H322 and H460, were used for in vitro studies. Apoptosis was examined by both flow cytometry and western blot. Signal transduction pathways in cells were assessed by western blot. Results: SC-1 induced apoptosis in association with reducing the phosphorylation of STAT3 (p-STAT3) in a dose- and time-dependent manner in four NSCLC cells lines (A549 H292 H322 and H460). SC-1 demonstrates dose-dependent anti-proliferation effects on cell viability in NSCLC cell lines on MTT assay. Increased amount of SC-1 represented improvement cell apoptosis by FACS in NSCLC cells. Western blot analysis showed SC-1 exhibit dose-dependent and time-dependent effect on cell apoptosis through inhibition of STAT3 with reducing p-STAT3 and the STAT3-regulating protein, Mcl-1, survivin and cyclinD1. Conclusions: SC-1 provides a proof of concept that targeting STAT3 signaling pathway is a novel approach for the treatment of EGFR wild type NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3764. doi:1538-7445.AM2012-3764