Gefitinib, but not erlotinib, is a possible inducer of Fra-1-mediated interstitial lung disease

Keio J Med. 2012;61(4):120-7. doi: 10.2302/kjm.2011-0009-oa.


Gefitinib is an anticancer drug developed to inhibit the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Two structurally-related EGFR tyrosine kinase inhibitors, gefitinib (Iressa) and erlotinib (Tarceva), are used as oral chemotherapy by patients with non-small-cell lung cancer. Immediately after introduction of gefitinib to clinical practice, interstitial lung disease was identified as a life-threatening adverse effect, although this condition can be well managed. It is still unclear whether gefitinib and other EGFR inhibitors induce similar adverse effects in lung. We previously established mouse models of interstitial lung disease in which gefitinib induces expression of Fosl1 (which encodes the AP-1 transcription factor Fra-1) in the presence of exogenous or endogenous Toll-like receptor ligands, leading to abnormal cytokine and chemokine expression. Here, we compared and monitored the effects of EGFR inhibitors gefitinib, erlotinib and AG1517 (PD153035) on the mRNA expression levels of Fosl1, Tnf and Ccl2. Unexpectedly, gefitinib, but not the other tyrosine kinase inhibitors, elicited the Fosl1 expression profile proposed to be predictive of interstitial lung disease, suggesting that gefitinib-induced interstitial lung disease is an off-target effect not elicited by erlotinib.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Disease Models, Animal
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Erlotinib Hydrochloride
  • Gefitinib
  • Gene Expression Regulation / drug effects
  • Lipopolysaccharides / pharmacology
  • Lung Diseases, Interstitial / chemically induced*
  • Lung Diseases, Interstitial / genetics
  • Lung Diseases, Interstitial / metabolism
  • Lung Diseases, Interstitial / pathology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred ICR
  • Primary Cell Culture
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-fos / genetics*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Quinazolines / adverse effects*
  • Quinazolines / pharmacology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism


  • Antineoplastic Agents
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Lipopolysaccharides
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-fos
  • Quinazolines
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • fos-related antigen 1
  • Erlotinib Hydrochloride
  • EGFR protein, mouse
  • ErbB Receptors
  • Gefitinib
  • 4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline