耐药是晚期结直肠癌(CRC)治疗失败的主要原因，KRAS突变作为CRC靶向治疗的重要分子标志物，是CRC获得性耐药和预后差的关键因素。本研究前期发现KRAS突变预后差且对西妥昔单抗等靶向药物耐受，而在KRAS突变型CRC中TCF7L2突变提示预后好且可以作为CRC独立预后指标。实验表明TCF7L2突变能增加西妥昔单抗等靶向药物对细胞的凋亡比例并且抑制转移，GSEA分析显示TCF7L2突变介导KRAS信号通路下调并且导致下游靶基因SMAD7异常高表达; 基于此，我们提出科学假说：在KRAS突变型CRC中TCF7L2突变通过介导SMAD7异常上调从而逆转KRAS突变导致的对西妥昔单抗耐受。本项目拟通过ChIP-sequence, Luciferase report，IC50及体内外等实验，阐明TCF7L2突变在KRAS突变型CRC中调控SMAD7耐药新机制，为寻找CRC耐药靶点提供新策略。

Drug resistance is the main reason for the failure of advanced colorectal cancer (CRC) treatment. As an important molecular marker of CRC targeted therapy, KRAS mutation is a key factor for acquired resistance and poor prognosis of CRC. Early studies revealed that KRAS mutations were found to have a poor prognosis and resistance to targeted drugs such as cetuximab. TCF7L2 mutations in KRAS mutant CRC suggest a good prognosis and can be used as an independent prognostic indicator for CRC. Experiments have shown that TCF7L2 mutation can increase the apoptosis rate of target drugs like cetuximab and reduce cell proliferation ability. GSEA analysis showed that TCF7L2 mutation mediates downregulation of the KRAS signal pathway and leads to abnormally high expression of downstream target gene SMAD7. We propose a scientific hypothesis: TCF7L2 mutation in KRAS mutant CRC reverses tolerance to targeted drugs caused by KRAS mutation by mediating the abnormal upregulation of SMAD7. This project intends to clarify a new mechanism for TCF7L2 mutations to regulate SMAD7 resistance in KRAS mutant CRC through ChIP-sequence, Luciferase report, IC50 and in vitro and in vivo experiments, and to provide a new strategy for finding targets for CRC resistance.