CSPG4/NG2促进甲状腺癌细胞对BRAFV600E激酶抑制剂耐药的机制研究

BRAFV600E突变是甲状腺癌中最常见的遗传变异，目前已经成为甲状腺癌的主要治疗靶点，但临床数据显示携带该突变的甲状腺癌患者对其特异性抑制剂的疗效不佳。我们前期研究发现，与癌旁组织相比，硫酸软骨素蛋白多糖4（CSPG4/NG2）在甲状腺癌组织中高表达。此外，在BrafV600E突变驱动的甲状腺癌转基因小鼠模型中，我们发现随着肿瘤的进展CSPG4/NG2的表达也随之升高。进一步研究证实，虽然敲除CSPG4/NG2并不影响甲状腺肿瘤的生长，但可显著增强肿瘤细胞对BRAF激酶抑制剂PLX4032的敏感性。由此，我们推测CSPG4/NG2可能参与调控甲状腺癌细胞对BRAF激酶抑制剂的耐药。在此基础上，本项目拟通过一系列的体内外实验阐明其具体的分子机制，并探索潜在的临床应用模式，从而为携带BRAFV600E突变的甲状腺癌患者的治疗提供新的思路和策略，具有重要的临床意义。

BRAFV600E is a constitutively active onco-kinase and is the most common genetic alteration in thyroid cancers, and has become a major therapeutic target; however, clinical benefit of some small-molecule inhibitors against this mutation is usually limited by short-lived responses and acquired resistance via heterogeneous feedback mechanisms. Our data demonstrated that increased expression of chondroitin sulfate proteoglycan 4 (CSPG4/NG2) was found in thyroid cancers compared to their adjacent non-cancerous thyroid tissues. In addition, we also found that the expression of CSPG4/NG2 gradually increased with tumor progression in BrafV600E-drived thyroid cancer mouse model. Further studies revealed that CSPG4/NG2 knockout almost did not affect tumor growth, but significantly enhanced the response of cancer cells to BRAFV600E specific inhibitor PLX4032. Thus, we speculate that CSPG4/NG2 may contribute to the resistance of thyroid cancer cells to BRAFV600E specific inhibitors. Based on these findings, in this project, we aimed to elucidate corresponding molecular mechanism by a series of in vitro and in vivo experiments, and explore potential clinical application patterns, thereby providing a new therapeutic strategy for thyroid cancer patients harboring BRAFV600E.