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Peer-reviewedCC BY 4.0Oncology Research

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
7 affiliations
  1. 1Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
  2. 2Department of Oncology and Radiotherapeutics, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic
  3. 3Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
  4. 4ARON Research Foundation ETS, Galleria del Commercio n. 6, Macerata, Italy
  5. 5Bahrain Defence Force Royal Medical Services, Riffa, Bahrain
  6. 6Medical Oncology Unit, Azienda Ospedaliera Universitaria Consorziale Policlinico di Bari, Bari, Italy
  7. 7Medical Oncology Unit, Macerata Hospital, Macerata, Italy
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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.

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Cite

BibTeXRIS
BibTeX
@article{sridharan2026overcoming,
  title = {{Overcoming the Shield: Mechanisms of Resistance to DNA Repair Inhibitors and Strategies to Restore Synthetic Lethality}},
  author = {Kannan Sridharan and Ondrej Fiala and Gowri Sivaramakrishnan and Mimma Rizzo and Matteo Santoni},
  journal = {Oncology Research},
  year = {2026},
  month = oct,
  doi = {10.32604/or.2026.081879},
  url = {https://doi.org/10.32604/or.2026.081879},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Overcoming the Shield: Mechanisms of Resistance to DNA Repair Inhibitors and Strategies to Restore Synthetic Lethality
AU  - Kannan Sridharan
AU  - Ondrej Fiala
AU  - Gowri Sivaramakrishnan
AU  - Mimma Rizzo
AU  - Matteo Santoni
PY  - 2026
DA  - 2026/10/28
JO  - Oncology Research
DO  - 10.32604/or.2026.081879
UR  - https://doi.org/10.32604/or.2026.081879
AB  - 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.
SN  - 0965-0407
SN  - 1555-3906
ER  -