Oncotarget

Research Papers:

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

Juan Zhou, Jinjing Wang, Yunyun Zeng, Xi Zhang, Qiaoting Hu, Jihua Zheng, Bei Chen, Bo Xie and Wei-Min Zhang _

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Oncotarget. 2015; 6:44332-44345. https://doi.org/10.18632/oncotarget.6293

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Abstract

Juan Zhou1,2,*, Jinjing Wang2,*, Yunyun Zeng2,*, Xi Zhang2, Qiaoting Hu2, Jihua Zheng2, Bei Chen2, Bo Xie2, Wei-Min Zhang2

1Department of Oncology, Guangzhou Clinical College of the Second Military Medical University, Guangzhou, Guangdong 510010, China

2Department 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-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.


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