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

Yosuke Togashi, Hidetoshi Hayashi, Kunio Okamoto, Soichi Fumita, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Kazuhiko Nakagawa, Kazuto Nishio

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)


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 1. μM 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.

Original languageEnglish
Pages (from-to)16-23
Number of pages8
JournalLung Cancer
Issue number1
Publication statusPublished - Apr 1 2015
Externally publishedYes


  • Cigarette smoking
  • Epidermal growth factor receptor mutation
  • Epidermal growth factor receptor tyrosine kinase inhibitor
  • Nicotine
  • Non-small cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research


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