Hypoxia induces resistance to EGFR inhibitors in lung cancer cells via upregulation of FGFR1 and the MAPK pathway

Lung Cancer
02/09/2020

Cancer Res. 2020 Sep 1:canres.1192.2020. doi: 10.1158/0008-5472.CAN-20-1192. Online ahead of print.

ABSTRACT

Development of resistance remains the key obstacle to the clinical efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). Hypoxia is a key microenvironmental stress in solid tumors associated with acquired resistance to conventional therapy. Consistent with our previous studies, we show here that long-term, moderate hypoxia promotes resistance to the EGFR TKI osimertinib (AZD9291) in the NSCLC cell line H1975, which harbors two EGFR mutations including T790M.


Hypoxia-induced resistance was associated with development of epithelial-mesenchymal transition (EMT) coordinated by increased expression of ZEB-1, an EMT activator. Hypoxia induced increased fibroblast growth factor receptor 1 (FGFR1) expression in NSCLC cell lines H1975, HCC827 and YLR086, and knockdown of FGFR1 attenuated hypoxia-induced EGFR TKI resistance in each line. Upregulated expression of FGFR1 by hypoxia was mediated through the MAPK pathway and attenuated induction of the pro-apoptotic factor BIM. Consistent with this, inhibition of FGFR1 function by the selective small molecular inhibitor BGJ398 enhanced EGFR TKI sensitivity and promoted upregulation of BIM levels. Furthermore, inhibition of MEK activity by trametinib showed similar effects. In tumor xenografts in mice, treatment with either BGJ398 or trametinib enhanced response to AZD9291 and improved survival. These results suggest that hypoxia is a driving force for acquired resistance to EGFR TKIs through increased expression of FGFR1. The combination of EGFR TKI and FGFR1 or MEK inhibitors may offer an attractive therapeutic strategy for NSCLC.