Abstract 736: Hypoxia-induced EGFR tyrosine kinase inhibitor resistance is associated with epithelial-mesenchymal transition in NSCLC

Abstract

Abstract The development of small molecule inhibitors specific for epidermal growth factor receptors (EGFR) with activating mutations has led to a dramatic shift in the treatment of non-small cell lung cancer (NSCLC) patients. Patients with NSCLC carrying such EGFR mutations often show prolonged responses when treated with first or second generation EGFR tyrosine kinase inhibitors (TKIs). However, most patients eventually develop resistance to EGFR TKIs. Hypoxia is a key micro-environmental stress in solid tumors that is associated with poor prognosis. Studies have linked hypoxia to therapy resistance, including radiation therapy and chemotherapy. In this study, we show that long-term, moderate hypoxia induces gefitinib resistance in the NSCLC cell line, HCC827, that harbors an activating EGFR mutation. The hypoxia-induced gefitinib resistance is associated with reduced BIM induction after gefitinib treatment when compared to normoxic HCC827 cells. In addition, in hypoxic HCC827 cells, gefitinib treatment induces N-cadherin expression, a mesenchymal marker, accompanied by downregulation of E-cadherin, an epithelial maker. These results suggest that epithelial-mesenchymal transition (EMT) may be involved in hypoxia induced gefitinib resistance. Wound healing migration assays further support that hypoxia induces HCC827 cell migration after gefitinib treatment. These results suggest that hypoxia may be a driving force for EGFR TKIs resistance potentially through EMT in NSCLC. Citation Format: Yuhong Lu, Peter M. Glazer. Hypoxia-induced EGFR tyrosine kinase inhibitor resistance is associated with epithelial-mesenchymal transition in NSCLC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 736.