title: Endothelial PAS domain-containing protein 1 confers TKI-resistance by mediating EGFR and MET pathways in non-small cell lung cancer cells.
abstract: Mutations 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)-1α. Here we report that endothelial PAS domain-containing protein 1 (EPAS1), with 48% sequence identity to HIF-1α, 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 knock-down 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 TKI-resistance 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.
authors.affiliation: a Department of Thoracic Surgery; Shijiazhuang No.1 Hospital ; Shijiazhuang , Hebei Province , China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhen
authors.forename: Jun-Feng
authors.initials: JF
authors.lastname: Liu
authors.forename: Jia-Bao
authors.initials: JB
authors.lastname: Liu
authors.forename: Ren-Feng
authors.initials: RF
authors.lastname: Wang
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Chu
authors.forename: Ya-Xiao
authors.initials: YX
authors.lastname: Zhang
authors.forename: Guo-Liang
authors.initials: GL
authors.lastname: Tan
authors.forename: Xiao-Jian
authors.initials: XJ
authors.lastname: Zhao
authors.forename: Bao-Lei
authors.initials: BL
authors.lastname: Lv
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D005784:Gene Amplification / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D066246:ErbB Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met; D000099162:Endothelial PAS Domain-Containing Protein 1; C000715470:MAS1 protein, human; C512478:EGFR protein, human; C491743:MET protein, human
keywords: EGFR; EGFR, epidermal growth factor receptor; EPAS1; EPAS1, endothelial PAS domain-containing protein 1; HIF)-1α., hypoxia-inducible factor; MET; NSCLC, non-small-cell lung cancer; TKI-resistance; TKIs, tyrosine kinase inhibitors; non-small cell lung cancer
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