Implication of epithelial-mesenchymal transition in IGF1R-induced resistance to EGFR-TKIs in advanced non-small cell lung cancer

// Juan Zhou 1, 2, * , Jinjing Wang 2, * , Yunyun Zeng 2, * , Xi Zhang 2 , Qiaoting Hu 2 , Jihua Zheng 2 , Bei Chen 2 , Bo Xie 2 , Wei-Min Zhang 2 1 Department of Oncology, Guangzhou Clinical College of the Second Military Medical University, Guangzhou, Guangdong 510010, China 2 Department of Oncology, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong 510010, China * These authors have contributed equally to this work Correspondence to: Wei-Min Zhang, e-mail: wmzhang79@126.com Keywords: epidermal growth factor receptor-tyrosine kinase inhibitors, epithelial-mesenchymal transition, type 1 insulin-like growth factor receptor, non-small cell lung cancer, drug resistance Received: May 21, 2015      Accepted: October 26, 2015      Published: November 05, 2015 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-naive 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.