Abstract 1877: Hypoxia induces EGFR inhibitor resistance in lung cancer cells by upregulation of fibroblast growth factor receptor 1 (FGFR1) via MAPK pathway

Abstract

Abstract The development of small molecule tyrosine kinase inhibitors (TKIs) specific for epidermal growth factor receptors (EGFRs) with activating mutations has led to a new paradigm in the treatment of non-small cell lung cancer (NSCLC) patients. However, most patients eventually develop resistance. Hypoxia is a key micro-environmental stress in solid tumors that is associated with poor prognosis due in part to acquired resistance to conventional therapy. In our previous study, we showed that long-term, moderate hypoxia promotes resistance to the EGFR TKI, gefitinib, in the NSCLC cell line, HCC827, which harbors an activating EGFR mutation. In this study, we found that hypoxia also induces third generation EGFR TKI, osimertinib (AZD9291), resistance in the NSCLC cell line, H1975, which had developed resistance to first and second generation of EGFR TKIs by harboring second EGFR mutation, T790M. Following growth in hypoxia, hypoxia-induced gefitinib resistant HCC827 clones and hypoxic H1975 cells show increased N-cadherin expression and decreased E-cadherin expression, characteristics of an epithelial-mesenchymal transition (EMT), coordinated by an increased expression of ZEB1, an EMT activator. Mechanistically, we show that hypoxia induces increased fibroblast growth factor receptor 1 (FGFR1) expression in HCC827 and H1975 cells, and that knockdown of the FGFR1 by shRNA can attenuate hypoxia induced EGFR TKI resistance in both HCC827 and H1975 cells. We also found the upregulated expression of FGFR1 by hypoxia is mediated through the MAPK pathway to lead to EGFR TKI resistance. In keeping with this, inhibition of FGFR1 function by the selective small molecular inhibitor, BGJ398, attenuates hypoxia-induced EGFR TKI resistance and promotes upregulation of BIM levels. Similarly, inhibition of MEK activity by the inhibitor, trametinib, shows similar effects. In vivo in tumor xenografts in mice, BGJ398 treatment or trametinib treatment suppresses tumor growth and enhances AZD9291 response. These results suggest that hypoxia is a driving force for acquired resistance to EGFR TKIs through increased FGFR1 expression and coordination of EMT in NSCLC. The combination of EGFR TKIs and FGFR1 or MEK inhibitors may offer an attractive therapeutic strategy for NSCLCs. Citation Format: Yuhong Lu, Yanfeng Liu, Sebastian Oeck, Gary J. Zhang, Peter M. Glazer. Hypoxia induces EGFR inhibitor resistance in lung cancer cells by upregulation of fibroblast growth factor receptor 1 (FGFR1) via MAPK pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1877.