Combined tamoxifen and gefitinib in non-small cell lung cancer shows antiproliferative effects

Biomed Pharmacother. 2010 Feb;64(2):88-92. doi: 10.1016/j.biopha.2009.06.010. Epub 2009 Oct 23.


Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is approved for clinical use in the treatment of non-small cell lung cancer (NSCLC). According to statistics, NSCLC patients who are female, have adenocarcinoma, or never smoked have a higher response rate to gefitinib treatment. This phenomenon could be due to the interaction between the estrogen receptor (ER) and EGFR. To test whether inhibition of the EGFR signaling pathway affects the antitumour effect of gefitinib, NSCLC cell lines were treated with gefitinib and tamoxifen, an ER antagonist. Cotreatment with gefitinib plus tamoxifen decreased the proliferation and increased the apoptosis of A549 and H1650 adencarcinoma cell lines, when compared with either drug alone. However, there was no effect on H520 cells (squamous cell carcinoma). Rapid activation of the EGFR pathway by both EGF and beta-E2 was observed in A549 cells. Additionally, EGFR and ERbeta expression was down-regulated in response to estrogen and EGF, respectively, but up-regulated in response to tamoxifen and genfitib, respectively. These results suggest that there is a functional cross-signaling between the EGFR and the ER pathways in NSCLC, possibly providing a rationale to combine gefitinib with anti-estrogen therapy for lung cancer treatment.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis / drug effects
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Drug Screening Assays, Antitumor
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Estrogen Receptor beta / antagonists & inhibitors
  • Estrogen Receptor beta / metabolism
  • Female
  • Gefitinib
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology*
  • Quinazolines / administration & dosage
  • Quinazolines / pharmacology*
  • Receptor Cross-Talk
  • Signal Transduction / drug effects
  • Tamoxifen / administration & dosage
  • Tamoxifen / pharmacology*


  • Estrogen Receptor beta
  • Quinazolines
  • Tamoxifen
  • ErbB Receptors
  • Gefitinib