title: Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR-mutated lung cancer via an EGFR signal.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Togashi
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan; Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan; Department of Medical Oncology, Kishiwada Municipal Hospital, Osaka, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan; Department of Medical Oncology, Kishiwada Municipal Hospital, Osaka, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan; Department of Medical Oncology, Kishiwada Municipal Hospital, Osaka, Japan.
authors.forename: Soichi
authors.initials: S
authors.lastname: Fumita
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Terashima
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Marco A
authors.initials: MA
authors.lastname: de Velasco
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Shuta
authors.initials: S
authors.lastname: Tomida
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan. Electronic address: knishio@med.kindai.ac.jp.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009538:Nicotine / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D011978:Receptors, Nicotinic / Q000378:metabolism; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D011978:Receptors, Nicotinic; D009538:Nicotine; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Cigarette smoking; Epidermal growth factor receptor mutation; Epidermal growth factor receptor tyrosine kinase inhibitor; Nicotine; Non-small cell lung cancer