Referenced in: none

Automatically associated channels: ClC4

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

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

Journal, date & volume: Lung Cancer, 2015 Apr , 88, 16-23

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25704955

Abstract
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.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.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.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.