TTK1-TPX2正反馈环路促进上皮性卵巢癌铂类耐受的机制及其干预研究

铂类药物耐受是上皮性卵巢癌（EOC）治疗面临的重大挑战，与同源重组修复（HR）活化有关，但具体调控机制仍不清楚。本课题组在COPS5促进EOC铂类耐药的基础上新发现，非洲爪蟾驱动蛋白样蛋白2靶蛋白（TPX2）在耐药进程中表达显著升高，下调其表达可抑制HR并逆转耐药，同时发现苏氨酸和酪氨酸激酶1（TTK1）与TPX2形成正反馈环路。本项目拟以EOC患者癌组织及细胞系、动物模型为对象，采用转录组联合ATAC测序、ChIP、Co-IP、磷酸化蛋白芯片等技术来明确TTK1-TPX2环路在HR活化和铂类耐药形成过程中的作用，探索TPX2下游分子网络并解析关键调控点，进而阐明该环路形成及其促进EOC耐药的分子机制；通过构建体内外模型,验证靶向TPX2策略对EOC铂类耐药的改善作用。本项目将从TTK1-TPX2轴这一全新视角揭示EOC铂类耐药机制，可望为临床控制EOC进展和改善患者预后提供新的思路。

Platinum-resistance remains a critical problem restricting the therapeutic efficiency in patients with epithelial ovarian cancer (EOC), which is related to the activation of homologous recombination (HR) repair pathway. However, the detailed regulatory mechanism of drug resistance remains to be elucidated. Based on the promoted platinum-resistance by COPS5 in the EOC, our project further identified that targeting protein for Xenopus kinesin-like protein 2 (TPX2) expression was significantly increased in the emerge of platinum-resistance, whereas the decreased TPX2 expression could inhibit HR activity and reverse platinum-resistance. We also found that threonine and tyrosine kinase 1 (TTK1) could form a positive feedback loop with TPX2. Based on cancer tissues of EOC patients, EOC cell lines, and animal models, transcriptome combined with ATAC sequencing, ChIP, Co-IP, phosphorylated protein chip and other technologies were used to clarify the roles of TTK1-TPX2 loop in the process of HR activation and the formation of platinum-resistance. Also, we aim to explore the downstream molecular network of TPX2 and further analyze the key regulatory nodules, intending to clarify the formation of this loop and the specific molecular mechanism of promoting EOC resistance. In addition, we evaluate whether the targeted TPX2 strategy could inhibit the platinum-resistance in EOC in vitro and in vivo experiments. Our project may provide novel insights into the mechanism of platinum-resistance in EOC from a new perspective of TTK1-TPX2 loop, and it is also expected to provide new ideas to control progression and improve prognosis in clinical EOC management.