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REVIEW

Overcoming the Shield: Mechanisms of Resistance to DNA Repair Inhibitors and Strategies to Restore Synthetic Lethality

Kannan Sridharan1, Ondrej Fiala2,3,4, Gowri Sivaramakrishnan5, Mimma Rizzo6, Matteo Santoni4,7,*
1 Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
2 Department of Oncology and Radiotherapeutics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic
3 Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
4 ARON Research Foundation ETS, Galleria del Commercio n. 6, Macerata, Italy
5 Bahrain Defence Force Royal Medical Services, Riffa, Bahrain
6 Medical Oncology Unit, Azienda Ospedaliera Universitaria Consorziale Policlinico di Bari, Bari, Italy
7 Medical Oncology Unit, Macerata Hospital, Macerata, Italy
* Corresponding Author: Matteo Santoni. Email: email
(This article belongs to the Special Issue: Targeting DNA Repair in Cancer)

Oncology Research https://doi.org/10.32604/or.2026.081879

Received 10 March 2026; Accepted 04 June 2026; Published online 29 June 2026

Abstract

The emergence of resistance to poly (ADP-ribose) polymerase (PARP) inhibitors poses a significant obstacle in treating cancers characterized by BReast CAncer gene (BRCA) mutations or homologous recombination deficiency. Despite the substantial clinical benefits brought by drugs such as olaparib, niraparib, and talazoparib, a substantial proportion of tumors ultimately develop resistance. The underlying mechanisms are diverse and include the reconstitution of homologous recombination via secondary BRCA reversion mutations, stabilization of replication forks, enhanced drug efflux mediated by p-glycoproteins, and structural or functional alterations in PARP1 itself. A thorough grasp of these resistance pathways is critical for the design of effective therapeutic interventions. Emerging strategies aimed at countering resistance involve combinatorial regimens incorporating inhibitors of Ataxia telangiectasia and Rad3-related (ATR), WEE1, checkpoint kinase 1 (CHK1), or immune checkpoint blockade, and other agents that target DNA damage response (DDR) networks. Furthermore, next-generation PARP inhibitors and optimized drug scheduling paradigms are under investigation to reestablish tumor sensitivity. Refined, biomarker-guided patient selection and advanced molecular surveillance may further optimize treatment outcomes and postpone the onset of resistance. This review offers a mechanism-centric synthesis of resistance to DNA repair inhibitors and the therapeutic strategies being developed to circumvent it.

Keywords

BRCA1/BRCA2 mutations; drug resistance; poly (ADP-ribose) polymerase (PARP) inhibitors; prostate cancer; synthetic lethality

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