肿瘤靶向治疗发展迅速，抗EGFR靶向治疗已应用于临床，但研究显示携带BRAFV600E突变型患者对EGFR抗体耐药。针对此问题科研人员研发了BRAF特异性抑制剂，然而临床实验发现部分患者出现耐药甚至促瘤作用，迫切需要新的治疗措施。课题组前期研究发现Mps1是癌基因BRAFV600E新作用靶点，BRAFV600E通过磷酸化修饰Mps1蛋白影响其稳定性、激酶活性，导致中心体过度复制、多级纺锤体出现，在肿瘤细胞染色体不稳定性中发挥重要作用。提示Mps1可能作为携带BRAFV600E突变型肿瘤患者新的治疗靶点。本项目拟在中国人结直肠癌、甲状腺癌中分析Mps1与BRAFV600E基因的相关性，利用逆转录病毒系统、Mps1激酶特异性抑制剂、RNAi等技术，探讨靶向抑制Mps1功能在携带BRAFV600E突变型恶性肿瘤中的治疗作用，为携带BRRAFV600E突变型恶性肿瘤治疗提供新的候选靶点及理论依据。

Molecular targeted therapy in metastatic tumors is rising worldwide. The therapeutic strategy to target the selected EGFR has been developed in clinical trial. However, it shows severe adverse effects in the treatment of patients harboring B-RAFV600E mutation. Although the oral BRAF inhibitors (such as vemurafenib) have remarkable clinical activity in metastatic melanomas with B-RAFV600E mutation, resistance to therapy invariably develops. The limitations of these agents emphasize the importance of developing novel treatment strategies. Our previous work identified a novel downstream target of B-RAFV600E, Mps1. We find that continuously activated B-RAFV600E signaling may be a possible mechanism for the deregulation of Mps1 stability and kinase activity in human tumors, and that persistent phosphorylation of Mps1 through B-RAFV600E signaling is a key event in disrupting the control of centrosome duplication and chromosome stability that may contribute to tumorigenesis. Our findings raise the possibility that targeting the oncogenic B-RAF and S281-phosphorylated Mps1, especially when used in combination could potentially provide great therapeutic opportunities for cancer treatment. This proposal aims to identify the correlation of B-RAFV600E and Mps1 in Chinese melanoma, colon cancers, and thyroid cancers. Moreover, as Mps1 has been identified as a novel target of B-RAFV600E in patients with melanoma, this proposal will investigate the possibility of a therapeutic role of Mps1 inhibition in patients with B-RAFV600E mutation through retrovirus infection, Mps1 inhibitor, and Mps1 siRNA.