New study data offer insight into how EGFR activating mutations promote tumor angiogenesis and aggressiveness in non-small cell lung cancer (NSCLC). Specifically, the research showed that EGFR-mutant NSCLC cells had a VEGF-dependent phenotype, and in tumor cells, EGFR was the dominant regulator of HIF-1α expression. By contrast, in EGFR wild-type NSCLC, hypoxia was the primary regulator of HIF-1α.
“These findings indicated that patients with EGFR mutations may represent a highly VEGF-dependent subgroup that may benefit from combined EGFR and VEGF blockade,” the study authors wrote.
To make these discoveries, the researchers analyzed the effect of EGFR inhibition on VEGF and HIF-1α in NSCLC models. In a panel of 110 NSCLC cell lines with or without activating EGFR mutations, VEGF RNA levels were significantly higher in EGFR-mutant NSCLC cell lines compared with wild-type cell lines (P =.02). However, this increased VEGF expression did not reflect a general upregulation of cytokines or angiogenic factors, as there was no significant difference in the expression of angiogenic factors not regulated by HIF-1α. “Together, these data suggest that mutant but not wild-type EGFR increase VEGF expression,” the investigators stated.
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In addition, cells with EGFR activating mutations had increased HIF-1α expression, with 1.5-fold greater levels of HIF-1α mRNA than cell lines expressing wild-type EGFR. HIF-1α levels were also higher in EGFR-mutant cell lines. An analysis examining regulation of HIF-1α also showed that in NSCLC cell lines with EGFR mutations, HIF-1α expression was predominantly regulated by EGFR signaling with blunted hypoxia.
“Uncoupling of HIF expression and hypoxia in cells expressing mutant EGFR demonstrates an important mechanism by which cells can upregulate HIF and its target genes in the absence of hypoxia,” the researchers wrote. “This aberrant upregulation can trigger an overall hypoxic gene signature within the tumor microenvironment creating pseudohypoxia, which has been proposed as a mechanism of EGFR inhibitor resistance.”
This finding has important biological implications, according to the investigators.
“In tumors driven primarily by the EGFR pathway, targeting HIF or key HIF-regulated genes (ie, VEGF) may further inhibit tumor growth and invasiveness beyond the effect of EGFR inhibition alone, and delay drug tolerance,” they wrote. “Moreover, VEGFR and EGFR activate common downstream signaling pathways including the PI3K/Akt and MAPK pathways in endothelial and tumor cells expressing VEGF receptors (VEGFR). Therefore, VEGF overexpression may further drive signal bypass-mediated resistance to EGFR [tyrosine kinase inhibitors], which is supported by preclinical findings that VEGF expression is further elevated in vivo following EGFR TKI resistance and that blockade of both VEGFR2 and EGFR has greater anti-tumor activity than the respective monotherapies.”
Disclosures: Some of the study authors disclosed financial relationships with the pharmaceutical industry and/or the medical device industry. For a full list of disclosures, please refer to the original study.
Reference
Nilsson MB, Robichaux J, Herynk MH, et al. Altered regulation of HIF-1α in naïve- and drug-resistant EGFR mutant NSCLC: implications for a VEGF-dependent phenotype. J Thorac Oncol. Published online December 9, 2020. doi:10.106/j.jtho.2020.11.022
