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

批准号:
81473645
项目类别:
面上项目
资助金额:
76.0 万元
负责人:
舒琦瑾
依托单位:
学科分类:
H3115.中医肿瘤学
结题年份:
2018
批准年份:
2014
项目状态:
已结题
项目参与者:
陈群伟、张晶、王彬彬、郦安琪、王海兵、单双双、吴志强、潘方舒、郭会
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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。
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.
非小细胞肺癌的发病和死亡率逐年攀升,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,但其仍对旁路激活耐药。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。本项目分别对PC9、PC9/R、A549、H1975、H1993进行体内、体外实验,各细胞干预组为南方红豆杉水提物组,阿法替尼组,克唑替尼组、红豆杉联合阿法替尼组、红豆杉联合克唑替尼组及两靶向药联合组,同时设置对照组。对细胞或组织进行CCK8、RT-PCR、Western-blot、免疫组化等实验,以明确南方红豆杉水提物对EGFR-TKIs耐药细胞株的调控作用及相关机制。体内外实验结果表明,对PC9、PC9/R、A549、H1975、 H1993细胞株,中药联合组较单药组能显著抑制细胞或移植瘤的增殖(P<0.05)。Western-blot及RT-PCR结果显示,中药联合组能抑制HGF/MET旁路及下游PI3K/AKT等信号通路(P<0.05)。因此,本项目初步明确南方红豆杉水提物克服EGFR-TKI(阿法替尼)得机制可能是抑制EGFR旁路HGF/MET通路的激活。
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DOI:--
发表时间:2017
期刊:中国中西医结合杂志
影响因子:--
作者:张武广;舒琦瑾
通讯作者:舒琦瑾
南方红豆杉通过调控Wnt/β-catenin/TCF-4阻断CD47/SIRPα信号轴增强PD-1/PD-L1免疫检查点抑制剂的疗效
- 批准号:--
- 项目类别:面上项目
- 资助金额:52万元
- 批准年份:2022
- 负责人:舒琦瑾
- 依托单位:
南方红豆杉水提物克服第三代EGFR-TKIs获得性耐药的机制研究
- 批准号:81873243
- 项目类别:面上项目
- 资助金额:62.0万元
- 批准年份:2018
- 负责人:舒琦瑾
- 依托单位:
南方红豆杉水提物调控T790M突变和c-Met基因扩增逆转人肺癌吉非替尼耐药机制的研究
- 批准号:81173247
- 项目类别:面上项目
- 资助金额:57.0万元
- 批准年份:2011
- 负责人:舒琦瑾
- 依托单位:
国内基金
海外基金
