Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR-mutated lung cancer via an EGFR signal. Issue 1 (April 2015)

• Record Type: Journal Article
• Authors: Togashi, Yosuke; Hayashi, Hidetoshi; Okamoto, Kunio; Fumita, Soichi; Terashima, Masato; de Velasco, Marco A.; Sakai, Kazuko; Fujita, Yoshihiko; Tomida, Shuta; Nakagawa, Kazuhiko; Nishio, Kazuto
• Is Part Of: Lung cancer. Volume 88:Issue 1(2015:Apr.)
• Page Start: 16
• Page End: 23
• Publication Date: 2015-04
• Subjects: Non-small cell lung cancer -- Epidermal growth factor receptor mutation -- Epidermal growth factor receptor tyrosine kinase inhibitor -- Nicotine -- Cigarette smoking; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2015.01.027
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR -mutated NSCLC. The resistance arises from the EGFR signal activation through nAChR. A smoking history is associated with a shorter PFS on EGFR-TKI treatment. 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. 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.