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

Juan Zhou1,2, Jinjing Wang2, Yunyun Zeng2

  • 1Department of Oncology, Guangzhou Clinical College of The Second Military Medical University, Guangzhou, Guangdong 510010, China.

Oncotarget
|November 12, 2015
PubMed

Insights

Insulin-like growth factor 1 receptor (IGF1R) activation drives epithelial-mesenchymal transition (EMT), causing resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). Targeting IGF1R and EMT may overcome this resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) affects 30-40% of non-small cell lung cancer (NSCLC) patients.
  • Epithelial-mesenchymal transition (EMT) and type 1 insulin-like growth factor receptor (IGF1R) activation are implicated in acquired EGFR-TKI resistance.

Purpose of the Study:

  • To investigate the role of EMT and IGF1R in acquired EGFR-TKI resistance in NSCLC cell lines.
  • To explore the therapeutic potential of targeting IGF1R and EMT in overcoming EGFR-TKI resistance.

Main Methods:

  • Utilized NSCLC cell lines with mutant (PC-9) or wild-type EGFR (H460), including EGFR-TKI-resistant variants (PC-9/GR, H460/ER).
  • Assessed the effects of IGF1R inhibition (SiIGF1R), IGF-1 stimulation, TGF-β1 induction of EMT, and E-cadherin overexpression on drug resistance and cellular morphology.
  • Evaluated changes in EMT phenotype and IGF1R expression in resistant cell lines compared to parental cells.

Main Results:

  • EGFR-TKI-resistant cells exhibited an EMT phenotype and increased IGF1R expression.
  • IGF1R inhibition reversed EMT and restored sensitivity to EGFR-TKIs in resistant cells.
  • IGF-1 induced EMT and resistance in naïve cells, while TGF-β1 induced EMT and decreased sensitivity. E-cadherin overexpression reversed resistance.

Conclusions:

  • IGF1R activation promotes acquired EGFR-TKI resistance in NSCLC by inducing EMT.
  • Targeting IGF1R and EMT presents a promising therapeutic strategy for advanced NSCLC with acquired resistance to EGFR-TKIs.
Keywords:
drug resistanceepidermal growth factor receptor-tyrosine kinase inhibitorsepithelial-mesenchymal transitionnon-small cell lung cancertype 1 insulin-like growth factor receptor

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