Epithelial to mesenchymal transition derived from repeated exposure to gefitinib determines the sensitivity to EGFR inhibitors in A549, a non-small cell lung cancer cell line

Lung Cancer. 2009 Feb;63(2):219-26. doi: 10.1016/j.lungcan.2008.05.017. Epub 2008 Jul 2.


Epithelial to mesenchymal transition (EMT) has been reported to be related with reduced sensitivity to EGFR tyrosine kinase (EGFR-TK) inhibitors. We performed this study to investigate whether this phenomenon would play a role in acquired resistance to gefitinib. In this study, we established a gefitinib-resistant subline (A549/GR), which was derived from the parental A549 cell line by chronic, repeated exposure to gefitinib. Compared with the A549 cells, the A549/GR cells were approximately 7.7-fold more resistant to gefitinib and they showed the cross-resistance against other EGFR-TK inhibitors, including CL-387,758, erlotinib and ZD6478. Phenotypic changes such as a spindle-cell shape and increased pseudopodia formation suggesting EMT was present in the A549/GR cells. These changes were accompanied by a decrease of E-cadherin and an increase of vimentin, which is a mesenchymal marker. In addition, the ability of invasion and migration was increased in the A549/GR cells. TGF-beta1 treatment for 72 h also induced EMT in the A549 cells and this transition led to resistance to gefitinib. Conversely, this was reversed through the removal of TGF-beta1. In conclusion, induction of EMT may contribute to the decreased efficacy of therapy in primary and acquired resistance to gefitinib.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Movement
  • Drug Resistance, Neoplasm
  • Epithelium / pathology*
  • ErbB Receptors / antagonists & inhibitors*
  • Gefitinib
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Mesoderm / pathology*
  • Neoplasm Invasiveness
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quinazolines / pharmacology*
  • Transforming Growth Factor beta1 / pharmacology


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Quinazolines
  • Transforming Growth Factor beta1
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • Gefitinib