卵巢癌（Ovarian cancer, OC）异质性显著但治疗手段单一。因此，针对不同类型的OC开发靶向药物将优化OC的治疗。近年来错配修复（Mismatch repair, MMR）基因缺陷被证实与OC发病相关。我们前期发现近10%的OC患者的癌细胞存在MMR蛋白表达缺陷，但其在正常细胞中表达正常。本项目利用癌细胞和正常细胞在MMR蛋白表达上的差异，以协同致死策略筛选能选择性杀伤MMR-细胞的药物。申请人已构建MMR-细胞模型，并经筛选发现Polo样激酶1（Polo-like Kinase 1，PLK1）抑制剂能选择性杀伤MMR-细胞，其机制和γH2AX诱导不足有关。拟开展的研究如下： 1. 在前期基础上进一步研究抑制 PLK1和MMR-的协同致死作用机制；2.在动物模型上验证PLK1抑制剂的治疗效果；3.检测靶蛋白在人OC组织中的表达。该研究有望为MMR-的OC患者提供靶向治疗的方向。

Epithelial ovarian cancer is the leading cause of death amongst gynaecological cancers. The majority of patients are diagnosed at a late stage and most eventually relapse and develop chemotherapy resistance. Therefore, to optimize ovarian cancer therapy, specific treatments that target molecular subtypes of ovarian cancer are required. Recent studies demonstrated that deficiency of mismatch repair (MMR) genes is associated with development of ovarian cancer. We have shown that nearly 10% ovarian cancer patients had MMR defects in their cancer.cells but not in their normal cells. This project aims to identify compounds that selectively kill ovarian cancer cells with MMR deficiency by the strategy of synthetical lethality. We have established the isogenic cell line model of MMR deficiency and found that inhibiting PLK1 is synthetically lethal with MMR deficiency. Based on our previous work, we are going to carry out the following study: 1. Investigate the mechanism of PLK1 and MMR-synthetical lethality at cellular level; 2. Validate the PLK1 and MMR-synthetical lethality in animal models; 3. Detect expression of target proteins in human ovarian cancer tissue. This may lead to a new, selective strategy of treating MMR deficient ovarian cancers.