南方红豆杉水提物抑制EGFR旁路HGF/MET通路抗EGFR-TKI耐药的机制研究

项目名称： 南方红豆杉水提物抑制EGFR旁路HGF/MET通路抗EGFR-TKI耐药的机制研究

项目编号： No.81473645

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 舒琦瑾

作者单位： 浙江中医药大学

项目金额： 76万元

中文摘要： 非小细胞肺癌的发病和死亡率逐年攀升，传统手段疗效已进入平台期。以表皮生长因子酪氨酸激酶抑制剂（EGFR-TKI）为主的分子靶向治疗疗效确切。但耐药不可避免。EGFR-TKI耐药机制主要有EGFR二次突变，旁路激活（约占20%）两点，针对前者，以阿法替尼为代表的不可逆EGFR-TKI已一线应用，可其仍对旁路激活耐药。故对EGFR旁路HGF/MET通路激活的NSCLC，可逆或不可逆的EGFR-TKIs均耐药。HGF/MET通路激活是EGFR旁路激活的主要途径，因此抑制其激活具重要意义。水煎剂为中药传统剂型，体现中医辨证论治精髓。本课题组既往研究表明南方红豆杉水提物联合吉非替尼能下调吉非替尼耐药株PI3K/AKT、JAK/STAT3、ERK1/2的表达，抑制其生长。基于此，本研究拟以MTT、Western-blot、PCR等方法探讨南方红豆杉水提物抑制EGFR旁路HGF/MET通路激活的机制。

中文关键词： 南方红豆杉；非小细胞肺癌；EGFR；旁路；HGF/MET通路；酪氨酸激酶抑制剂；耐药

英文摘要： The incidence and mortality of non-small cell lung cancer have increased steadily, at the same time, traditional treatments cannot reach better therapeutic effect. Currently, targeting therapy, especially epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have reached inspirable treatment effect and are widely used in clinic. However, almost all patients who have used EGFR-TKI will get drug resistance. The mechanism of EGFR-TKI resistance can be divided to secondary mutation of EGFR and activation of EGFR bypass ( 20% EGFR-mutated tumors that have been pretreated with an EGFR TKI). Afatinib and other irreversible EGFR-TKIs has overcome EGFR T790M, which is the most frequent secondary mutation in EGFR but still resistant to patients with EGFR bypass activation. Thus, both reversible or irreverisble EGFR-TKIs are resistant to NSCLC which EGFR bypss are activated. HGF/MET signaling pathway is an important part of activation of EGFR bypass. Inhibiting the activation of this pathway has important clinical and practical sense. Decoction of Chinese materia medica is a traditional dosage form used in clinic, which reflects the essence of treatment based on syndrome differentiation. Our recent researches indicate aqueous extract taxus chinensis var.mairei (ATEC) combined with Gefitinib can restrain cancer cell growth and significantly down regulate PI3K/AKT、JAK/STAT3、ERK1/2 expression in cell line which resistant to Gefitinib. Based on above mentioned preliminary work, this research determines to explore the mechanism of inhibition of ATEC to EGFR bypass HGF/MET signaling pathway on overcoming EGFR-TKI resistance by using methods such as MTT, Westen-Blot, PCR, et al.

英文关键词： Aqueous Extract of Taxus chinensis var.mairei;non-small cell lung cancer;EGFR bypass HGF/MET pathway;EGFR-TKI;drug resistance