Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR-mutated lung cancer via an EGFR signal

Lung Cancer. 2015 Apr;88(1):16-23. doi: 10.1016/j.lungcan.2015.01.027. Epub 2015 Feb 7.


Background: Some of patients with non-small cell lung cancer (NSCLC) harboring somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations) show poor responses to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) treatment. Cigarette smoking is the strongest documented risk factor for the development of lung cancer. Nicotine, while not carcinogenic by itself, has been shown to induce proliferation, angiogenesis, and the epithelial-mesenchymal transition; these effects might be associated with EGFR-TKI resistance.

Materials and methods: PC-9 and 11_18 cell lines (EGFR-mutated NSCLC cell lines) were cultured with 1μM nicotine for 3 months and were designated as PC-9/N and 11_18/N cell lines, respectively. The sensitivities of these cell lines to EGFR-TKI were then tested in vitro. Moreover, the association between the smoking status and the progression-free survival (PFS) period was investigated in patients with EGFR-mutated NSCLC who were treated with gefitinib.

Results: The PC-9/N and 11_18/N cell lines were resistant to EGFR-TKI, compared with controls. The phosphorylation of EGFR in these cell lines was reduced by EGFR-TKI to a smaller extent than that observed in controls, and a higher concentration of EGFR-TKI was capable of further decreasing the phosphorylation. Clinically, smoking history was an independent predictor of a poor PFS period on gefitinib treatment.

Conclusions: Chronic nicotine exposure because of cigarette smoking mediates resistance to EGFR-TKI via an EGFR signal. Smoking cessation is of great importance, while resistance may be overcome through the administration of high-dose EGFR-TKI.

Keywords: Cigarette smoking; Epidermal growth factor receptor mutation; Epidermal growth factor receptor tyrosine kinase inhibitor; Nicotine; Non-small cell lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Cell Line, Tumor
  • Disease-Free Survival
  • Drug Resistance, Neoplasm / drug effects*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics*
  • ErbB Receptors / metabolism
  • Female
  • Gefitinib
  • Humans
  • Kaplan-Meier Estimate
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / mortality
  • Male
  • Middle Aged
  • Mutation
  • Nicotine / pharmacology*
  • Quinazolines / pharmacology*
  • Quinazolines / therapeutic use
  • Receptors, Nicotinic / metabolism
  • Signal Transduction
  • Smoking / adverse effects


  • Antineoplastic Agents
  • Quinazolines
  • Receptors, Nicotinic
  • Nicotine
  • EGFR protein, human
  • ErbB Receptors
  • Gefitinib