Yosuke Togashi1, Hidetoshi Hayashi2, Kunio Okamoto3, Soichi Fumita3, Masato Terashima1, Marco A de Velasco1, Kazuko Sakai1, Yoshihiko Fujita1, Shuta Tomida1, Kazuhiko Nakagawa4, Kazuto Nishio5. 1. Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan. 2. 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. 3. Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan; Department of Medical Oncology, Kishiwada Municipal Hospital, Osaka, Japan. 4. Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan. 5. Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan. Electronic address: knishio@med.kindai.ac.jp.
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 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.
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.
Authors: Jamie R Friedman; Stephen D Richbart; Justin C Merritt; Kathleen C Brown; Nicholas A Nolan; Austin T Akers; Jamie K Lau; Zachary R Robateau; Sarah L Miles; Piyali Dasgupta Journal: Pharmacol Ther Date: 2018-10-03 Impact factor: 13.400