BRAF-SUMOylation作为BRAF（V600E）转移性结直肠癌治疗新靶点的实验研究

BRAF V600E是常见的BRAF突变，通常预后很差，大部分患者均会产生不同程度的耐药。因此，深入了解BRAF V600E mCRC患者的耐药机制，寻找治疗新靶点，对于改善mCRC的治疗效果至关重要。研究发现，BRAF的SUMO修饰在具有V600E突变的肠癌细胞株中显著高表达，其主要修饰位点恰巧为其盐桥形成的关键位点K507。鉴于V600E与K507形成的盐桥结构对其激酶活性的重要作用，我们提出：SUMO化修饰可能影响BRAF V600E的激酶活性，对其发挥致癌作用至关重要。同时，临床治疗BRAF V600E mCRC的药物能增加BRAF SUMO修饰水平。BRAF SUMO修饰可能通过增加形成同源/异源二聚体的能力，激活下游信号，引发耐药。本研究将揭示SUMO化修饰在BRAF V600E激酶活性发挥中的关键作用及其介导的耐药新机制，另辟蹊径为mCRC靶向药物开发及临床诊治提供新的思路。

BRAF V600E is a common BRAF mutation with poor prognosis. Most patients have different degrees of drug resistance. Therefore, in-depth understanding of the drug resistance mechanism of BRAF V600E mCRC patients and looking for new therapeutic targets are essential to improve the therapeutic effect of mCRC. It was found that the SUMOylation of BRAF was highly expressed in colorectal cancer cell lines with V600E mutation, and its main modification site happened to be the key site of its salt bridge formation, k507. In view of the important role of the salt bridge structure formed by V600E and k507 in its kinase activity, we suggest that SUMO modification may affect the kinase activity of BRAF V600E, which is crucial for its carcinogenic effect. At the same time, the clinical treatment of BRAF V600E mCRC can increase the level of BRAF SUMO modification. BRAF SUMO modification may increase the ability of BRAF to form homo/ heterodimer, activate downstream signal and induce drug resistance. This study will reveal the key role of SUMOylation in BRAF V600E kinase activity and the new mechanism of drug resistance mediated by SUMOylation, and provide new ideas for the development of mCRC targeted drugs and clinical diagnosis and treatment.