SMAD4V354L功能性突变增强非小细胞肺癌多西他赛化疗敏感性的分子机制研究

肺癌发病率和死亡率均居世界首位，其中80%-85%为非小细胞肺癌。多西他赛和铂类药物联合化疗是中晚期非小细胞肺癌的一线治疗方案，但多数患者化疗后出现耐药，导致化疗失败。因此，如何克服多西他赛耐药问题成为国内外学者研究的热点和难点。本项目前期临床研究发现带有SMAD4V354L突变患者应用多西他赛后无病生存期和总生存期明显延长，预后较好，但具体机制尚未明确。该突变位点未见国内外报道，本课题拟从该突变位点切入开展：(1)通过ZDOCK模型模拟突变后与SMAD2,3对接情况。(2)通过构建带有SMAD4V354L突变细胞系及转基因小鼠，质谱、Chip-sep分析等突变后对下游信号的调控机制。(3)找出SMAD4V354L突变后影响的关键蛋白及对微管的多重调控作用，论证多西他赛增效分子机制。阐明SMAD4V354L突变后多西他赛增效分子机制，为以SMAD4为靶点的抗肿瘤药物研发奠定基础。

The incidence and mortality of lung cancer rank first in the world, of which 80%-85% are non-small cell lung cancer. Docetaxel and platinum-based chemotherapy are the first-line treatment options for advanced non-small cell lung cancer, but most patients develop resistance after several cycles of chemotherapy, which leads to chemotherapy failure. Therefore, finding a way to overcome docetaxol multidrug resistance become difficult for scholars. Previous study indicated that patients with SMAD4V354L mutations were found to present improved disease-free survival and overall survival after chemotherapy with docetaxel and carboplatin, but the mechanism has not yet been determined. The mutation site has not been reported. Based on this findings, the work will be carried out: (1) The docking situation of Smad4V354L and SMAD2,3 will be illustrated through the ZDOCK model. (2) The mutant cell line and transgenic mice with SMAD4V354L will be constructed to study the regulation of downstream signals after mutation. (3) To find out the key proteins affected by the mutation, and to explore the multiple regulation of key proteins and microtubules after SMAD4V354L mutation, and to demonstrate the mechanism of enhancing the docetaxel therapeutic effect. To elucidate the molecular mechanism of synergism of docetaxel after Smad4V354L mutation would be significant for the development of antitumor drugs targeting Smad4.