Clinical application of PARP inhibitors in ovarian cancer: from molecular mechanisms to the current status

Abstract

As a kind of gynecological tumor, ovarian cancer is not as common as cervical cancer and breast cancer, but its malignant degree is higher. Despite the increasingly mature treatment of ovarian cancer, the five-year survival rate of patients is still less than 50%. Based on the concept of synthetic lethality, poly (ADP- ribose) polymerase (PARP) inhibitors target tumor cells with defects in homologous recombination repair(HRR), the most significant being the target gene Breast cancer susceptibility genes(BRCA). PARP inhibitors capture PARP-1 protein at the site of DNA damage to destroy the original reaction, causing the accumulation of PARP-DNA nucleoprotein complexes, resulting in DNA double-strand breaks(DSBs) and cell death. PARP inhibitors have been approved for the treatment of ovarian cancer for several years and achieved good results. However, with the widespread use of PARP inhibitors, more and more attention has been paid to drug resistance and side effects. Therefore, further research is needed to understand the mechanism of PARP inhibitors, to be familiar with the adverse reactions of the drug, to explore the markers of its efficacy and prognosis, and to deal with its drug resistance. This review elaborates the use of PARP inhibitors in ovarian cancer.

DNA Double-Strand Break Repair Inhibitors: YU238259, A12B4C3 and DDRI-18 Overcome the Cisplatin Resistance in Human Ovarian Cancer Cells, but Not under Hypoxia Conditions

“…DRIs as potential anticancer drugs have been tested in clinical trials and introduced into the treatment scheme of some particular cancers [23]. The most striking example is PARP inhibitors; however, they are limited to killing cancer cells that show a BRCAness phenotype and are not able to act successfully in other types of cancer [24,25].…”

Endometriosis-Associated Ovarian Cancer: From Molecular Pathologies to Clinical Relevance

“…Especially patients with BRCA1/2-mutated tumors benefit from targeted therapies with PARP inhibitors due to the concept of synthetic lethality [193,194]: Tumor cells with a BRCA mutation lack the ability to repair DNA double-strand breaks via homologous recombination and are thus dependent on repairing DNA damage via the single-strand break (SSB) repair pathway [195]. By inhibiting the ribozyme PARP, mainly involved in SSB repair, tumor cells with BRCA mutations cannot repair DNA damage, leading to the accumulation of DNA damage and subsequently cell death without affecting normal cells [195].…”

Patient-derived functional immuno-oncology platform identifies responders to ATR inhibitor and immunotherapy combinations in ovarian cancer

“…Despite the successful response to initial treatment, recurrent disease often develops within the first three years. Poly (ADP-ribose) polymerase inhibitors (PARPi) have improved patient’s outcome when used as a first-line or maintenance therapy, particularly in patients with homologous recombination deficiency (HRD), and or sensitivity to platinum-based chemotherapy ( 3 ). However, 35-45% of the patients discontinue the treatment due to innate or acquired resistance to PARPi ( 4, 5 ), suggesting that novel combination strategies are required to overcome resistance to PARPi.…”