{
  "abstract": "Poly (ADP-ribose) polymerase inhibitors (PARPi) have transformed the treatment landscape for homologous recombination-deficient (HRD) cancers, particularly those harboring BRCA1/2 mutations, including breast, ovarian, prostate, and pancreatic cancers, by exploiting the synthetic lethality induced by HR deficiency (HRD) and utilizing HRD status as a predictive biomarker. Nevertheless, intrinsic as well as acquired resistance limits their long-term effectiveness. Resistance often develops as a result of several complex mechanisms including the restoration of homologous recombination (HR), stabilization of the replication fork, enhanced drug efflux, loss of PARP1 expression, epigenetic modifications, and changes in the DNA damage response signaling. BRCA1/2-mutant cells, deficient in HR, become reliant on alternative repair pathways like classical non-homologous end joining (c-NHEJ) and microhomology-mediated end joining (MMEJ). Emerging evidence indicates the importance of replication-induced gaps in single-stranded DNA (ssDNA) and alternative pathways of DNA repair in defining PARPi sensitivity and resistance. This review aims to provide a comprehensive analysis of the established and emerging molecular mechanisms of PARPi resistance, and compensatory DNA repair pathways such as MMEJ. In addition to highlighting resistance pathways, the review also discusses strategies focusing on targeting repair mechanisms and replication stress signaling by using novel drugs targeting DNA polymerase theta (POLQ). It subsequently discusses preclinical advancements and ongoing clinical trials. Through linking the molecular determinants of resistance to the translational status and limitations of the latest therapies, this review offers a comparative framework for understanding resistance mechanisms and strategies to restore PARPi sensitivity in cancers with HRD.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA",
    "Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA",
    "Department of Biotechnology, National Institute of Technology Warangal, Hanamkonda 506004, Telangana, India",
    "Bioclues.org, Kukatpally, Hyderabad 500072, Telangana, India",
    "School of Biotechnology, Kalinga Institute of Industrial Technology, (KIIT) Deemed to be University, Bhubaneswar 751024, Odisha, India",
    "Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada",
    "Department of Food Science and Technology, The Ohio State University, Columbus, OH 43210, USA"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Kousalya Lavudi",
      "orcid": "0000-0002-3213-3938"
    },
    {
      "affs": [
        2
      ],
      "name": "Malavika Sunita Renjith"
    },
    {
      "affs": [
        3
      ],
      "name": "Charan PSVV",
      "orcid": "0000-0003-2634-578X"
    },
    {
      "affs": [
        4
      ],
      "name": "Rekha Rani Kokkanti",
      "orcid": "0000-0001-6015-2629"
    },
    {
      "affs": [
        5
      ],
      "name": "Prashant Pandey",
      "orcid": "0000-0003-0700-914X"
    },
    {
      "affs": [
        6
      ],
      "name": "Srikanth Ponneganti"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2h7arcc8te4v5.bib",
  "cited_by": 0,
  "doi": "10.3390/ijms27219814",
  "fulltext_url": null,
  "id": "2h7arcc8te4v5",
  "issns": [
    "1422-0067"
  ],
  "landing_url": "https://www.mdpi.com/1422-0067/27/21/9814",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [],
  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-01",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/2h7arcc8te4v5.ris",
  "sources": [
    {
      "first_seen": "2026-11-05T00:20:58Z",
      "native_id": "10.3390/ijms27219814",
      "source": "crossref",
      "url": "https://www.mdpi.com/1422-0067/27/21/9814"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "issn:1422-0067",
      "subfield": "general"
    }
  ],
  "title": "DNA Repair Pathways as Determinants of PARP Inhibitor Resistance and Therapeutic Targets in Cancer",
  "title_text": "DNA Repair Pathways as Determinants of PARP Inhibitor Resistance and Therapeutic Targets in Cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T00:21:14Z",
  "url": "https://research.draconitic.com/paper/2h7arcc8te4v5",
  "venue": "International Journal of Molecular Sciences",
  "versions": []
}