Back to Search
Start Over
Altered Regulation of HIF-1α in Naive- and Drug-Resistant EGFR-Mutant NSCLC: Implications for a Vascular Endothelial Growth Factor-Dependent Phenotype
- Source :
- J Thorac Oncol
- Publication Year :
- 2020
-
Abstract
- 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-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 with EGFR wild-type cells. In EGFR-mutant cells, EGFR, not hypoxia, was the dominant regulator of 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 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-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 and VEGF, and the pathways were no longer EGFR-regulated. This supports VEGF targeting in EGFR-mutant tumors in the EGFR inhibitor–naive and refractory settings.
- Subjects :
- 0301 basic medicine
Pulmonary and Respiratory Medicine
Vascular Endothelial Growth Factor A
Lung Neoplasms
Regulator
Article
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cell Line, Tumor
Medicine
Animals
Humans
Epidermal growth factor receptor
EGFR inhibitors
biology
business.industry
Hypoxia-Inducible Factor 1, alpha Subunit
Phenotype
Blockade
Vascular endothelial growth factor
ErbB Receptors
030104 developmental biology
Oncology
chemistry
Hypoxia-inducible factors
Tumor progression
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Cancer research
biology.protein
business
Subjects
Details
- ISSN :
- 15561380
- Volume :
- 16
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
- Accession number :
- edsair.doi.dedup.....a347722305180934dcd434a28711f75b