Altered regulation of HIF-1α in naïve- and drug-resistant EGFR mutant NSCLC: implications for a VEGF-dependent phenotype

Abstract Introduction Treatment of patients with EGFR mutant NSCLC with vascular endothelial growth factor (VEGF) inhibitors in combination with EGFR inhibitors provides 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-1α 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-1α. Results NSCLC cells with EGFR activating mutations exhibited altered regulation of VEGF compared to EGFR wild-type cells. In EGFR mutant cells, EGFR, not hypoxia, was the dominant regulator or HIF-1α and VEGF. NSCLC tumor models bearing classical or exon 20 EGFR mutations were more sensitive to VEGF inhibition than EGFR wild-type tumors, and combination of VEGF and EGFR inhibition delayed tumor progression. In models of acquired EGFR inhibitor resistance, while VEGF remained overexpressed, the hypoxia-independent expression of HIF-1α was delinked from EGFR signaling, and EGFR inhibition no longer diminished HIF-1α or VEGF expression. Conclusions In EGFR mutant NSCLC, EGFR signaling is the dominant regulator of HIF-1α and VEGF in a hypoxia-independent manner, hijacking an important cellular response regulating tumor aggressiveness. Cells with acquired EGFR inhibitor resistance retained elevated expression of HIF-1α/VEGF, and the pathways was no longer EGFR-regulated. This supports VEGF targeting in EGFR mutant tumors in the EGFR inhibitor naive and refractory settings.