title: Implication of epithelial-mesenchymal transition in IGF1R-induced resistance to EGFR-TKIs in advanced non-small cell lung cancer.
abstract: The underlying mechanisms for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in about 30%-40% of non-small cell lung cancer (NSCLC) patients remain elusive. Recent studies have suggested that activation of epithelial-mesenchymal transition (EMT) and type 1 insulin-like growth factor receptor (IGF1R) is associated with acquired EGFR-TKIs resistance in NSCLC. Our study aims to further explore the mechanism of EMT and IGF1R in acquired EGFR-TKIs resistance in NSCLC cell lines with mutant (PC-9) or wild-type EGFR (H460). Compared to parental cells, EGFR-TKIs-resistant PC-9/GR and H460/ER cells displayed an EMT phenotype and showed overexpression of IGF1R. SiIGF1R in PC-9/GR and H460/ER cells reversed EMT-related morphologies and reversed their resistance to EGFR-TKIs. Exogenous IGF-1 alone induced EMT in EGFR-TKIs-naïve PC-9 and H460 cells and increased their resistance against EGFR-TKIs. Inducing EMT by TGF-β1 in PC-9 and H460 cells decreased their sensitivity to EGFR-TKIs, whereas reversing EMT by E-cadherin overexpression in PC-9/GR and H460/ER cells restored their sensitivity to EGFR-TKIs. These data suggest that IGF1R plays an important role in acquired drug resistance against EGFR-TKIs by inducing EMT. Targeting IGF1R and EMT may be a potential therapeutic strategy for advanced NSCLC with acquired EGFR-TKIs resistance.
authors.affiliation: Department of Oncology, Guangzhou Clinical College of The Second Military Medical University, Guangzhou, Guangdong 510010, China.|Department of Oncology, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong 510010, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Oncology, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong 510010, China.
authors.forename: Jinjing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Oncology, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong 510010, China.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Oncology, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong 510010, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Oncology, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong 510010, China.
authors.forename: Qiaoting
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Oncology, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong 510010, China.
authors.forename: Jihua
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Oncology, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong 510010, China.
authors.forename: Bei
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Oncology, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong 510010, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Xie
authors.affiliation: Department of Oncology, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong 510010, China.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D015820:Cadherins; C000597236:IGF1R protein, human; D047428:Protein Kinase Inhibitors; D017451:Receptors, Somatomedin; D053773:Transforming Growth Factor beta1; D007334:Insulin-Like Growth Factor I; C512478:EGFR protein, human; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1
keywords: drug resistance; epidermal growth factor receptor-tyrosine kinase inhibitors; epithelial-mesenchymal transition; non-small cell lung cancer; type 1 insulin-like growth factor receptor