卵巢癌是致死率最高的妇科恶性肿瘤，传统的治疗方式是肿瘤细胞减灭术和以铂类药物为基础的联合化疗，随着卵巢癌发病机制的研究深入，分子靶向治疗也不断取得新的进展，靶向多聚ADP核糖聚合酶的PARP抑制剂就是新兴的抗癌药物。但PARP抑制剂同样也面临着肿瘤耐药性的问题，如何克服耐药以及扩大其临床应用范围是目前精准治疗的难题。我们通过全基因组CRISPR/Cas9慢病毒文库筛选，发现抑制CLK1后可明显逆转PARP抑制剂的耐药，并研究发现CLK1可调控CtIP的表达，引起同源重组修复途径缺陷，造成DNA损伤。本课题拟解析抑制CLK1后下调CtIP造成同源重组修复缺陷的分子机理；利用PDX模型探讨CLK1抑制剂逆转PARP抑制剂耐药的抗肿瘤作用；旨在为卵巢癌分子靶向治疗提供新思路。

Ovarian cancer is one of the most common gynecological malignant tumor. The traditional treatment is cytoreductive surgery and platinum-based combination chemotherapy. With the research of the pathogenesis of ovarian cancer, molecular targeted therapy is also constantly developing. PARP inhibitors targeting poly ADP ribose polymerase are emerging anticancer drugs. However, PARP inhibitors are also facing the problem of tumor resistance. How to overcome drug resistance and expand the scope of clinical application is the current problem of precision treatment. We took advantage of the whole genome CRISPR/Cas9 lentivirus library screening strategy and found that inhibition of CLK1 can significantly reverse the resistance of PARP inhibitors, and identified that CLK1 can regulate the expression of CtIP, causing defects in homologous recombination and causing DNA damage. This study aims to analyze the molecular mechanism of down-regulation of CtIP induced by CLK1 to cause the homologous recombination deficiency, and to explore the anti-tumor effect of CLK1 inhibitors by reversing the resistance of PARP inhibitors by PDX model, providing new ideas for molecular targeted therapy of ovarian cancer.