Abstract

Ovarian cancer is one of the most lethal gynecologic malignancies reported throughout the world. The initial, standard-of-care, adjuvant chemotherapy in epithelial ovarian cancer is usually a platinum drug, such as cisplatin or carboplatin, combined with a taxane. However, despite surgical removal of the tumor and initial high response rates to first-line chemotherapy, around 80% of women will develop cancer recurrence. Effective strategies, including chemotherapy and new research models, are necessary to improve the prognosis. The replication stress response (RSR) is characteristic of the development of tumors, including ovarian cancer. Hence, RSR pathway and DNA repair proteins have emerged as a new area for anticancer 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 inhibitors with DNA-damaging compounds for ovarian cancer therapy, as well as the new platforms used for optimizing ovarian cancer therapy.

Highlights

  • Ovarian cancer is considered to be one of the most lethal gynaecologic malignancies worldwide

  • Almost all of the type II carcinomas, i.e. 96%, have TP53 mutation [6] and around half of high-grade serous ovarian carcinomas (HGSOCs) carry an alteration in homologous recombination (HR) pathway genes, most commonly in breast cancer gene (BRCA) 1/2 [7]

  • 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

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Summary

Introduction

Ovarian cancer is considered to be one of the most lethal gynaecologic malignancies worldwide. 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 briefly characterizes the rationale of therapies combining these inhibitors, as well as recent updates/advances in those therapies in vitro and in clinical trials. In BRCA mutated cancer cells, PARP inhibition leads to tumor cell death, as a result of synthetic lethality According to this assumption, PARPi blocks the base excision repair (BER) through F-Box DNA helicase 1 (Fbh1)-dependent Rad regulation [46]. Talazoparib, a PARPi, enhances trapping of PARP1 in DSBs, leading to decreased NHEJ and leukemia cell death [49, 50] This agent is currently under clinical evaluation in patients with deleterious BRCA 1/2 mutation-associated ovarian cancer who have had prior PARP inhibitor treatment (NCT02326844). Progression-free survival was longer by around 3 months in the olaparib with chemotherapy

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