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.
Highlights
Acquired drug resistance has become a bottleneck in the treatment of advanced non-small cell lung cancer (NSCLC) using epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) [1,2,3]
To further evaluate whether activation of the IGF1R pathway was the major mechanism underlying acquired drug resistance, we targeted silencing of IGF1R using siRNA technology in PC-9/ GR and H460/ER cells
Knockdown of IGFIR significantly decreased the IC50 of gefitinib and erlotinib in PC-9/GR and H460/ER cells, respectively, suggesting that IGFIR may play an important role in restoring their sensitivity to gefitinib or erlotinib (Figure 1D)
Summary
Acquired drug resistance has become a bottleneck in the treatment of advanced non-small cell lung cancer (NSCLC) using epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) [1,2,3]. The known mechanisms underlying this acquired drug resistance include T790M mutation [4, 5] and amplification of MET genes [6]. These mechanisms account for about 60–70% of acquired drug resistance. Recent studies show that the activation of epithelialmesenchymal transition (EMT) and type 1 insulin-like growth factor receptor (IGF1R) is associated with acquired drug resistance against EGFR-TKIs in NSCLC [7, 8]. The exact mechanisms of IGF1R-induced acquired EGFR-TKIs resistance remain to be elucidated
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