Abstract
Relevance. PARP inhibitors (PARPi), have emerged as a significant development in the treatment of high-grade serous ovarian cancer that is associated with mutations in BRCA1/2 and genes of other homologous recombination proteins. These drugs exploit synthetic lethality by disrupting mechanism of repair of single-stranded DNA breaks. In the absence of a functioning homologous recombination system, this leads to the accumulation of double-stranded DNA breaks and the death of tumor cells. Despite the proven effectiveness of PARPi, acquired resistance has been demonstrated to limit the duration of the response. Systematization of the gained knowledge about the molecular mechanisms, clinical and pharmacological properties of PARPi is crucial for the discovery of new approaches to predicting the effectiveness of therapy, overcoming resistance and other breakthroughs in the ovarian cancer targeted therapy.
Objective. A review of the literature is necessary to facilitate a more profound comprehension of the mechanisms of action of PARPi and the development of tumour resistance.
Material and methods. The present paper analyses publications from the past decade, focusing on the molecular mechanisms of PARPi’s action within cells and the processes underlying resistance to these drugs. It provides data on pharmacokinetics and a brief overview of the landmark randomized clinical trials of PARPi. The present literature review drew upon the PubMed (https://pubmed.ncbi.nlm.nih.gov/) and Google Scholar (https://scholar.google.com/) databases. The search was conducted using the following keywords: «PARP», «PARPi», «pharmacodynamics», «pharmacokinetics», «molecular mechanisms of action», «resistance», and «phase III trials». The analysis included experimental studies elaborating on the molecular mechanisms of action of PARP and PARPi, review articles synthesizing the extant data, randomized clinical trials confirming the efficacy of PARPi in treating patients with ovarian cancer and BRCA1/2 mutations or homologous recombination deficiency (HRD), as well as Russian and international guidelines from professional societies current as of March 2026. The analysis did not include case reports on the use of PARPi or studies on the use of PARPi in malignant tumors of other localization.
Results. This literature review presents data regarding the molecular mechanisms of PARP function within the cell. Their role in the repair of single-strand and double-strand DNA breaks is also discussed, as well as the principles of action of PARPi and the effects they induce in malignant tumors. The pharmacodynamic and pharmacokinetic properties of PARPi are discussed, as are the evidence base for the use of these drugs in clinical practice by oncologists and the possible causes of resistance to PARPi.
Conclusion. Further research into the mechanisms of the action of PARPi in cells, as well as the tumor resistance to these drugs, will provide the foundation for the development of combination strategies involving PARPi. These strategies will, in turn, expand the possibilities for personalized treatment of ovarian cancer.
Authors and affiliations
https://elibrary.ru/qaqedl
E.I. Ivanova(1, 2), A.L. Chernyshova(1, 2), V.G. Sisakyan(2), S.N. Tamkovich(1, 2)
1-E.N. Meshalkin National Research Medical Center of the Ministry of Health of the Russian Federation, Rechkunovskaya str., 15,
Novosibirsk, 630055, Russian Federation; 2-Novosibirsk State University, Pirogova str., 1, Novosibirsk, 630090, Russian Federation
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