Abstract 4103: IL-6 dynamics regulate neuroendocrine transformation in gefitinib acquired resistance EGFR mutant lung cancer cells

Abstract

Abstract Transformation to small-cell lung cancer (SCLC, one of aggressive neuroendocrine [NE] tumor) is reported when activating epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer acquired resistance to tyrosine kinase inhibitors (TKI, such as gefitinib). IL-6 activation confers to acquire TKI resistance and associates with p53 and RB inactivation those are SCLC hallmark changes. Whether NE transformation could phenocopy in isogenic acquired resistance cell line and the role of IL-6 in this process remain unknown. We established 827GRs (including 827GR, 827GR+ and 827GR.M6) acquired resistance to gefitinib from HCC827 cells by long term stepwise treated with gefitinib and they still had EGFR exon 19 deletion without acquired T790M. 827GR was parental resistance line with unstable gefitinib resistance in drug-free medium by passage. We maintained 827GR in medium with or without 1μM gefitinib over 6 months to generate stable clones: 827GR+ and 827GR.M6. 827GRs had SCLC hallmark changes, i.e., inactivation of p53, RB and Notch by western blot and gene set enrichment analysis. Compared to HCC827, 827GRs were more sensitive to cisplatin and etoposide but not paclitaxel. IL-6 level was positive correlated with gefitinib resistance among 827GRs by cytokine array and ELISA. Interestingly, among 827GRs, 827GR.M6 harbored low IL-6 secretion had obviously NOTCH-ASCL1-DLL3 alteration, high NE marker expression and significant inter-rater agreement with selected Byers’ SCLC gene signature than high IL-6 secretion 827GR+, suggesting IL-6 dynamics might regulate NE marker expression. IL-6 genetic manipulation in HCC827 and 827GR+ also demonstrated this phenomenon. Moreover, IL-6 dynamics correlate with NE expression also showed in patient derived lung cancer cell line in published microarray dataset (GSE64322). In conclusion, our work demonstrated activating EGFR mutant lung cancer acquired resistance to TKI with NE transformation could phenocopy in isogenic cell line model and IL-6 dynamics might regulate this process. Citation Format: Shang-Yin Wu, Hsuan-Heng Yeh, Chun-Hua Hung, Chien-Chung Lin, Wen-Pin Su, Wu-Chou Su. IL-6 dynamics regulate neuroendocrine transformation in gefitinib acquired resistance EGFR mutant lung cancer cells [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 4103. doi:10.1158/1538-7445.AM2017-4103