Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy

Farmer, Hannah; McCabe, Nuala; Lord, Christopher J.; Tutt, Andrew N. J.; Johnson, Damian A.; Richardson, Tobias B.; Santarosa, Manuela; Dillon, Krystyna J.; Hickson, Ian; Knights, Charlotte; Martin, Niall M. B.; Jackson, Stephen P.; Smith, Graeme C. M.; Ashworth, Alan

doi:10.1038/nature03445

Cited by 6,683PARP inhibition in cancer therapyDNA Repair MechanismsBRCA gene mutations in cancer

Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy

Farmer, Hannah, McCabe, Nuala, Lord, Christopher J., Tutt, Andrew N. J., Johnson, Damian A., Richardson, Tobias B., Santarosa, Manuela, Dillon, Krystyna J. +6 more·2005·Nature

DOI 10.1038/nature03445

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Abstract

BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.

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BRCA-mutated cancer cells are selectively sensitive to agents that require homologous recombination repair, such as PARP1 inhibitors.
“Thus, BRCA-mutated cancer cells are selectively sensitive to agents that require repair of double-strand breaks by homologous recombination, such as PARP1 inhibitors [5–7].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [6]

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Authors: Farmer, H., McCabe, N., Lord, C. J., Tutt, A. N. J., Johnson, D. A., Richardson, T. B., Santarosa, M., Dillon, K. J., Hickson, I., Knights, C., Martin, N. M. B., Jackson, S. P., Smith, G. C. M., & Ashworth, A.
Affiliations: Cancer Research UK (GB)
Institute of Cancer Research (GB)
Guy's Hospital (GB)
University of Cambridge (GB)
Corresponding author: Smith, Graeme C. M.
Ashworth, Alan
ORCID: Lord, Christopher J.
Tutt, Andrew N. J.
Santarosa, Manuela
Hickson, Ian
Martin, Niall M. B.
Jackson, Stephen P.
Smith, Graeme C. M.
Ashworth, Alan
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2005-04
Volume: 434
Issue: 7035
Pages: 917-921
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature03445
OpenAlex: W1973268287
Cited by: 6,683
References: 24
Citations by year: 2026: 271 · 2025: 346 · 2024: 356 · 2023: 454 · 2022: 443 · 2021: 502 · 2020: 460 · 2019: 382 · 2018: 381 · 2017: 353 · 2016: 358 · 2015: 315 · 2014: 312 · 2013: 292 · 2012: 262
FWCI: 68.30
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Research Portal (King's College London) (submittedVersion)
Funders: Cancer Research UK
National Cancer Institute (F31CA260794)
Topics: Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
Keywords: BRCA1, BRCA2, PARP inhibitors, homologous recombination, base excision repair, synthetic lethality, breast cancer, DNA double-strand break repair, chromosomal instability, cell cycle arrest, apoptosis, targeted cancer therapy
MeSH terms: Poly(ADP-ribose) Polymerase Inhibitors, Animals, Antineoplastic Agents, Cell Survival, DNA Damage, DNA Repair, Mice, Nude, Models, Biological, Mutation, Neoplasms, Poly(ADP-ribose) Polymerases, Substrate Specificity, Apoptosis, Genes, BRCA1, Xenograft Model Antitumor Assays, Genes, BRCA2, Mice

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Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy

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