The phosphorylation of CHK1 at Ser317 and Ser345 after checkpoint signaling is regulated by ATR, and thus, phosphorylation at Ser345 fosters relocalization or retention of the protein in the nucleus . drug development. Although clinical trials have shown poly (ADP-ribose) polymerase inhibitors (PARPi) response rates of around 40% in women who carry a mutation in the BRCA1/2 genes, PARPi is responsible for tumor suppression, but not for complete tumor regression. Recent reports suggest that cells with impaired homologous recombination (HR) activities due to mutations in TP53 gene or specific DNA repair proteins are specifically sensitive to ataxia telangiectasia and Rad3-related protein (ATR) inhibitors. Replication stress activates DNA repair checkpoint proteins (ATR, CHK1), which prevent further DNA damage. This review describes the use of DNA repair checkpoint inhibitors as single agents and strategies combining these Rabbit polyclonal to Claspin inhibitors with DNA-damaging compounds for ovarian cancer therapy, as well as the new platforms used for optimizing ovarian cancer therapy. strong class=”kwd-title” Keywords: ATR kinase, CHK1, ovarian cancer, PARP, replication stress, targeted therapy Introduction Ovarian cancer is considered to be one of the most lethal gynaecologic malignancies worldwide. It is the seventh most common cancer and the fifth leading cause of cancer-related deaths . As a result of the absence of formal screening and the continued lack of early detection methods, the majority (around 80%) of patients are diagnosed at an advanced stage (III/IV) . The Fiacitabine 5-year survival rate of patients with high-grade serous ovarian carcinomas (HGSOCs) still ranges between 35 and 40% . In 2019 in the USA, an estimated 22,530 women were diagnosed with ovarian cancer and 13,980 died from the disease . Ovarian tumors can be divided into two types: type I ovarian cancers are composed of mucinous, endometrioid and low-grade serous carcinomas, while type II tend to grow more aggressively and include carcinosarcomas, undifferentiated carcinomas Fiacitabine and high-grade serous carcinomas . Moreover, almost all of the type II carcinomas, i.e. 96%, have TP53 mutation  and around half of HGSOCs carry an alteration in homologous recombination (HR) pathway genes, most commonly in breast cancer gene (BRCA) 1/2 . Women carrying mutations in these genes have a lifetime risk of developing ovarian cancer of 36 to 60% for BRCA1 and 16 to 27% for BRCA2 . The initial, standard-of-care, adjuvant chemotherapy in epithelial ovarian cancer (EOC) is usually a platinum drug, such as cisplatin or carboplatin, combined with a taxane, usually paclitaxel . Cisplatin interferes with the DNA repair mechanism by crosslinking the purine Fiacitabine bases of the DNA, and thus inducing apoptosis of cancer cells . The standard regimen for advanced ovarian cancer has been expanded with bevacizumab, a recombinant humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF) . Other promising angiogenesis inhibitors are sorafenib and Fiacitabine sunitinib [12, 13]. Since the addition of bevacizumab to the combination of standard chemotherapeutics, many other targeted anticancer agents have been studied in the hope of increasing the effectiveness of ovarian cancer treatment. Ovarian cancer cells often acquire resistance to common chemotherapy drugs such as cisplatin. If a tumor recurs within 6 months of cisplatin treatment, it is considered to be platinum-resistant [14, 15]. The aim of this article is to review the current knowledge of the targeting of DNA repair pathways in ovarian cancer. This review describes the use of DNA repair checkpoint inhibitors, especially poly (ADP-ribose) polymerase inhibitors (PARPi), ataxia telangiectasia and Rad3-related protein inhibitors (ATRi) and checkpoint kinase 1 inhibitors (CHK1i), as monotherapy/single agents, and their role in the treatment of patients with BRCAmut ovarian cancer. It also briefly characterizes the rationale of therapies combining these inhibitors, as well as recent updates/advances in those therapies in vitro and in clinical trials. Replication stress and cell cycle disturbances in ovarian cancer Increased understanding of the tumor repair pathways has revealed their significance in the sensitivity of cells to chemotherapeutic agents. DNA damage signalling pathways have a central role in detecting DNA damage and regulating its repair. Regulation of cellular responses to interference in these pathways by numerous extrinsic and intrinsic genotoxic agents leads to genomic instability and thus to cell death . Replication stress is defined as perturbations in cell replication. In defence against disorders in the course of DNA biosynthesis, cells have developed a network.