Endothelial PAS domain-containing protein 1 confers TKI-resistance by mediating EGFR and MET pathways in non-small cell lung cancer cells

Abstract

Abbreviations: EGFR, epidermal growth factor receptor; NSCLC, non-small-cell lung cancer; TKIs, tyrosine kinase inhibitors; EPAS1, endothelial PAS domain-containing protein 1; HIF)-1a., hypoxia-inducible factorMutations in epidermal growth factor receptor (EGFR) rendering it constitutively active is one of the major causes for metastatic non-small-cell lung cancer (NSCLC), and EGFR-targeted therapies utilizing tyrosine kinase inhibitors (TKIs) are often used clinically as the first-line treatment. But approximately half of NSCLC patients develop resistance to these therapies, where the MET proto-oncogene is amplified by EGFR through the hypoxia-inducible factor (HIF)-1a. Here we report that endothelial PAS domain-containing protein 1 (EPAS1), with 48% sequence identity to HIF-1a, specifically binds to TKI-resistant T790M EGFR, but not to wild-type EGFR, in NSCLC cell lines. Expression of EPAS1 enhances amplification of MET when simultaneously expressed with T790M EGFR but not with wild-type EGFR, and this enhancement is independent of ligand binding domain of EGFR. MET amplification requires EPAS1, since EPAS1 knockdown reduced MET levels. When NSCLC cells expressing T790M EGFR were treated with TKIs, reduced EPAS1 levels significantly enhanced the drug effect, whereas over-expression of EPAS1 increased the drug resistant effect. This EPAS1-dependent TKI-resistance was abolished by knocking-down MET, suggesting that EPAS1 does not cause TKIresistance itself but functions to bridge EGFR and MET interactions. Our findings suggest that EPAS1 is a key factor in the EGFR-MET crosstalk in conferring TKI-resistance in NSCLC cases, and could be used as a potential therapeutic target in TKI-resistant NSCLC patients.

MicroRNA‐383 is a tumor suppressor in human lung cancer by targeting endothelial PAS domain‐containing protein 1

“…To the best of our knowledge, the only one that identified the upstream factor of EPAS1 in not only lung but also any type of human cancer. Interestingly, EPAS1 was also recently found to be responsible for the resistance of NSCLC to treatment by using tyrosine kinase inhibitors, which warrants further investigations to explore whether miR‐383 is also acting as an upstream factor of tyrosine kinase inhibitor‐resistant NSCLC, and whether this process is mediated by EPAS1 as well.…”

Multi-Omics Analysis Reveals a HIF Network and Hub Gene EPAS1 Associated with Lung Adenocarcinoma

“…Sequencing of hub genes identified a new locus in EPAS1 that reached genome-wide significance and was validated in the largest lung cancer consortium, providing additional evidence that the HIFs-EGFR-HDAC4-TERT network is associated with NSCLC adenocarcinoma. Further, a recent study reported that EPAS1 could specifically bind to tyrosine kinase inhibitor (TKI)-resistant T790 M EGFR in NSCLC cell lines and enhance amplification of MET [ 46 ]. These findings suggest that EPAS1 is a key factor in EGFR-MET crosstalk in conferring TKI resistance in NSCLC cases and provide in vitro support of the HIFs-EGFR-HDAC4-TERT network.…”

MicroRNA-300 targets hypoxia inducible factor-3 alpha to inhibit tumorigenesis of human non-small cell lung cancer

“…Two HIF2α alleles, rs4953354 and rs13419896, were also shown to act as potential biomarker in lung cancer [32,33]. In a recent study, HIF2α also played important roles in tyrosine kinase inhibitor-resistant NSCLC cells [34].…”