miR-223 reverses the resistance of EGFR-TKIs through IGF1R/PI3K/Akt signaling pathway

Int J Oncol. 2016 May;48(5):1855-67. doi: 10.3892/ijo.2016.3401. Epub 2016 Feb 19.


Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, is a critical issue for the treatment of EGFR mutant-positive non-small cell lung cancer (NSCLC). Recent evidence supports the role of microRNA-223 (miR‑223) in modulating chemotherapeutic drug sensitivity, but its role in the resistance to EGFR-TKIs in NSCLC remains unclear. To this end, we investigated the involvement of miR‑223 in erlotinib resistance, using two pairs of TKI-sensitive or resistant cell lines, PC9 vs PC9/ER, and HCC827 vs HCC827/ER, as well as PC9/CD133+, which are lung cancer stem-like cells derived from PC9 cells. Downregulation of miR‑223 expression in PC9/ER and PC9/CD133+ cells was detected, and the reverse correlation of miR-233 and insulin-like growth factor 1 receptor (IGF1R) in these cells was also revealed. Next, levels of IGF1R mRNA and p-Akt were significantly reduced in miR‑223 stably transfected PC9/ER and PC9/CD133+ cells. However, the sensitivity of PC9/ER and PC9/CD133+ cells to erlotinib was partially restored, after overexpression of miR‑223 in those cells. Similar results were also observed in vivo. Furthermore, miR‑223-mediated inhibition of the IGF1R/PI3K/Akt signaling pathway may have been reversed by the agonist of IGF1R in miR‑223 transfected cells. Our findings indicated that downregulation of miR‑223, which can induce activation of the IGF1R/phosphatidylinositol 3-kinase (PI3K)/Akt pathway in PC9/ER and PC9/CD133+ cells, may be responsible for the resistance of PC9/ER and PC9/CD133+ cells to erlotinib, suggesting that miR‑223 is a potential therapeutic target for overcoming EGFR-TKIs resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Cell Line, Tumor
  • Down-Regulation*
  • Drug Resistance, Neoplasm*
  • Erlotinib Hydrochloride / pharmacology*
  • Humans
  • Lung Neoplasms / genetics*
  • Male
  • Mice
  • MicroRNAs / genetics*
  • Neoplasm Transplantation
  • Protein Kinase Inhibitors / pharmacology
  • Receptor, IGF Type 1
  • Receptors, Somatomedin / genetics
  • Signal Transduction / drug effects


  • Antineoplastic Agents
  • IGF1R protein, human
  • MIRN223 microRNA, human
  • MicroRNAs
  • Protein Kinase Inhibitors
  • Receptors, Somatomedin
  • Erlotinib Hydrochloride
  • Receptor, IGF Type 1