Altered Regulation of HIF-1α in Naive- and Drug-Resistant EGFR-Mutant NSCLC: Implications for a Vascular Endothelial Growth Factor-Dependent Phenotype

Introduction: The treatment of patients with EGFR-mutant NSCLC with vascular endothelial growth factor (VEGF) inhibitors in combination with EGFR inhibitors provides a greater benefit than EGFR inhibition alone, suggesting that EGFR mutation status may define a patient subgroup with greater benefit from VEGF blockade. The mechanisms driving this potentially enhanced VEGF dependence are unknown.Methods: We analyzed the effect of EGFR inhibition on VEGF and HIF-1 alpha in NSCLC models in vitro and in vivo. We determined the efficacy of VEGF inhibition in xenografts and analyzed the impact of acquired EGFR inhibitor resistance on VEGF and HIF-1 alpha.Results: NSCLC cells with EGFR-activating mutations exhibited altered regulation of VEGF compared with EGFR wild-type cells. In EGFR-mutant cells, EGFR, not hypoxia, was the dominant regulator of HIF-1 alpha and VEGF. NSCLC tumor models bearing classical or exon 20 EGFR mutations were more sensitive to VEGF inhibition than EGFR wild-type tumors, and a combination of VEGF and EGFR inhibition delayed tumor progression. In models of acquired EGFR inhibitor resistance, whereas VEGF remained overexpressed, the hypoxia-independent expression of HIF-1 alpha was delinked from EGFR signaling, and EGFR inhibition no longer diminished HIF-1 alpha or VEGF expression.Conclusions: In EGFR-mutant NSCLC, EGFR signaling is the dominant regulator of HIF-1 alpha and VEGF in a hypoxiaindependent manner, hijacking an important cellular response regulating tumor aggressiveness. Cells with acquired EGFR inhibitor resistance retained elevated expression of HIF-1 alpha and VEGF, and the pathways were no longer EGFR-regulated. This supports VEGF targeting in EGFRmutant tumors in the EGFR inhibitor-naive and refractory settings. (C) 2020 Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer.