Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR-mutated lung cancer via an EGFR signal
Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR-mutated lung cancer via an EGFR signal
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DOI：
10.1016/j.lungcan.2015.01.027
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发表时间：
2015-04-01
期刊：
影响因子：
5.3
通讯作者：
Nishio, Kazuto
中科院分区：
文献类型：
--
作者：
Togashi, Yosuke;Hayashi, Hidetoshi;Nishio, Kazuto
背景资料：一些携带表皮生长因子受体基因体细胞激活突变（EGFR突变）的非小细胞肺癌（NSCLC）患者对EGFR-酪氨酸激酶抑制剂（EGFR-TKI）治疗的反应较差。吸烟是有记录的导致肺癌发生的最强风险因素。尼古丁，而不是致癌本身，已被证明是诱导增殖，血管生成，和上皮间质转化，这些影响可能与EGFR-TKI resistance.Materials和方法：PC-9和11-18细胞系（EGFR突变的NSCLC细胞系）培养3个月，1 μ M尼古丁，分别命名为PC-9/N和11-18/N细胞系。然后在体外测试这些细胞系对EGFR-TKI的敏感性。结果：与对照组相比，PC-9/N和11-18/N细胞株对EGFR-TKI耐药。EGFR-TKI降低这些细胞系中EGFR磷酸化的程度低于对照组，且更高浓度的EGFR-TKI能够进一步降低磷酸化。在临床上，吸烟史是一个独立的预测不良PFS期对吉非替尼treatment.Conclusions：慢性尼古丁暴露，因为吸烟介导耐药EGFR-TKI通过EGFR信号。戒烟是非常重要的，而耐药性可以通过高剂量EGFR-TKI的管理来克服。(c)2015爱思唯尔爱尔兰有限公司版权所有。
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 mu M 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. (c) 2015 Elsevier Ireland Ltd. All rights reserved.