Activation of the FGF2-FGFR1 autocrine pathway: a novel mechanism of acquired resistance to gefitinib in NSCLC

Mol Cancer Res. 2013 Jul;11(7):759-67. doi: 10.1158/1541-7786.MCR-12-0652. Epub 2013 Mar 27.


Patients with non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutations initially respond to EGFR-tyrosine kinase inhibitors (TKI) but eventually experience relapse. Acquired resistance to EGFR-TKIs is strongly associated with patient mortality. Thus, elucidation of the mechanism of acquired resistance to EGFR-TKIs is of great importance. In this study, gefitinib-resistant cell line models were established by long-term exposure to gefitinib using the gefitinib-sensitive lung cancer cell lines, PC9 and HCC827. Expression analyses indicated that both FGFR1 and FGF2 were increased in PC9 gefitinib-resistant (PC9 GR) cells as compared with PC9 naïve (PC9 na) cells. Importantly, proliferation of gefitinib-resistant cells was dependent on the FGF2 -FGFR1 pathway. Mechanistically, inhibition of either FGF2 or FGFR1 by siRNA or FGFR inhibitor (PD173074) restored gefitinib sensitivity in PC9 GR cells. These data suggest that FGF2 -FGFR1 activation through an autocrine loop is a novel mechanism of acquired resistance to EGFR-TKIs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Autocrine Communication / drug effects*
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Clone Cells
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Synergism
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Fibroblast Growth Factor 2 / antagonists & inhibitors
  • Fibroblast Growth Factor 2 / metabolism*
  • Gefitinib
  • Humans
  • Lung Neoplasms
  • Models, Biological
  • Pyrimidines / pharmacology
  • Quinazolines / pharmacology*
  • RNA, Small Interfering / metabolism
  • Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism*
  • Signal Transduction / drug effects*


  • PD 173074
  • Pyrimidines
  • Quinazolines
  • RNA, Small Interfering
  • Fibroblast Growth Factor 2
  • ErbB Receptors
  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1
  • Gefitinib