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Oncotarget. 2015 Dec 29;6(42):44332-45. doi: 10.18632/oncotarget.6293.

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

Author information

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.

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.

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

PMID:
26554308
PMCID:
PMC4792560
DOI:
10.18632/oncotarget.6293
[Indexed for MEDLINE]
Free PMC Article

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