Abstract 5872: Stat3 feedback activation-induced PTGIS expression is associated with acquired resistance to EGFR-TKI in lung cancer

Abstract

Abstract Targeted cancer therapies can effectively promote tumor regression in clinical responses. Eventually, most tumors develop resistance to these drugs. Stat3 activation has been suggested as one of the mechanisms that cause acquired resistance to EGFR-tyrosin kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC). However, the underlying molecular mechanisms are not well studied. In this study, we found that treatment of gefitinib (EGFR-TKI) in NSCLC cell lines harboring EGFR-TKI sensitive mutation induced feedback activation of Stat3 in a time- and dose-dependent manner. High levels of IL-6 were detected in the conditioned medium of gefitinib-treated cells by cytokine array and were confirmed by ELISA. We demonstrated that IL-6 treatment could induce Stat3 activation and conditioned medium treatment-induced Stat3 activation was suppressed by IL-6 neutralizing antibody. We also demonstrated that gefitinib treatment-induced IL-6 secretion could be inhibited by knockdown of Stat3 expression. Moreover, pharmacological inhibition and genetic inhibition of Stat3 activation increased cell cytotoxicity of gefitinib in both PC9 and HCC827 cells that harboring EGFR-TKI sensitive mutation. Our data suggested that gefitinib treatment could induce activation of IL-6/Stat3 signaling loop and modulate cell cytotoxicity of gefitinib. Microarray and Ingenuity Pathway Analysis (IPA) analysis revealed prostaglandin I2 synthase (PTGIS) as a downstream target gene of IL-6/Stat3 signaling and PTGIS was up-regulated by gefitinib treatment. The induction of PTGIS by gefitinib via Stat3 feedback activation was confirmed in vitro genetically and pharmacologically. Moreover, we showed that cotreatment with PTGIS inhibitor improves the efficacy of EGFR inhibition in PC9 and HCC827 cells. Importantly, high expression of PTGIS was found in gefitinib-resistant PC9 cells (PC9/gef) compared with gefitinib-sensitive PC9 cells. Targeting PTGIS was also effective in decreasing viability of cells with acquired resistance to gefitinib in PC9/gef cells. Taken together, our study indicated that Stat3 feedback activation-induced PTGIS expression participates in modulating gefitinib efficacy and Stat3/PTGIS inhibition could potentially overcome acquired resistance to gefitinib in NSCLC. Note: This abstract was not presented at the meeting. Citation Format: Hsuan-Heng Yeh, Shang-Yin Wu, Chun-Hua Hung, Wu-Chou Su. Stat3 feedback activation-induced PTGIS expression is associated with acquired resistance to EGFR-TKI in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5872. doi:10.1158/1538-7445.AM2017-5872