Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase

Bryant, Helen E.; Schultz, Niklas; Thomas, Huw D.; Parker, Kayan M.; Flower, Dan; Lopez, Elena; Kyle, Suzanne; Meuth, Mark; Curtin, Nicola J.; Helleday, Thomas

doi:10.1038/nature03443

Cited by 5,198PARP inhibition in cancer therapyDNA Repair MechanismsBRCA gene mutations in cancer

Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase

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Bryant, Helen E., Schultz, Niklas, Thomas, Huw D., Parker, Kayan M., Flower, Dan, Lopez, Elena, Kyle, Suzanne, Meuth, Mark +2 more·2005·Nature

DOI 10.1038/nature03443

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Abstract

Poly(ADP-ribose) polymerase (PARP1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Nevertheless, PARP1-/- mice are viable, fertile and do not develop early onset tumours. Here, we show that PARP inhibitors trigger gamma-H2AX and RAD51 foci formation. We propose that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair. Furthermore, we show that BRCA2-deficient cells, as a result of their deficiency in homologous recombination, are acutely sensitive to PARP inhibitors, presumably because resultant collapsed replication forks are no longer repaired. Thus, PARP1 activity is essential in homologous recombination-deficient BRCA2 mutant cells. We exploit this requirement in order to kill BRCA2-deficient tumours by PARP inhibition alone. Treatment with PARP inhibitors is likely to be highly tumour specific, because only the tumours (which are BRCA2-/-) in BRCA2+/- patients are defective in homologous recombination. The use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumour, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment.

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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 [5]
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Abstract 3708: Targeting synthetic lethality with PARP inhibition in colorectal cancer
Augustine, T. A., Maitra, R., Zhang, J., et al. (2016) · Cancer Research · doi:10.1158/1538-7445.am2016-3708
Abstract 1566: DNA damage generated by transcription-replication conflicts explains the synthetic lethality of PARP inhibitors with homologous recombination deficiency
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Abstract 2744: Synthetic lethal killing of RAD54B-deficient cancer cells by PARP1 silencing and inhibition
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Discovery of 4-Hydroxyquinazoline Derivatives as Small Molecular BET/PARP1 Inhibitors That Induce Defective Homologous Recombination and Lead to Synthetic Lethality for Triple-Negative Breast Cancer Therapy
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Sirtuin inhibition is synthetic lethal with BRCA1 or BRCA2 deficiency
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Authors: Bryant, H. E., Schultz, N., Thomas, H. D., Parker, K. M., Flower, D., Lopez, E., Kyle, S., Meuth, M., Curtin, N. J., & Helleday, T.
Affiliations: University of Sheffield (GB)
Stockholm University (SE)
Newcastle University (GB)
Corresponding author: Helleday, Thomas
ORCID: Bryant, Helen E.
Thomas, Huw D.
Curtin, Nicola J.
Helleday, Thomas
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2005-04-14
Volume: 434
Issue: 7035
Pages: 913-917
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature03443
OpenAlex: W2009007206
Cited by: 5,198
References: 26
Citations by year: 2026: 213 · 2025: 256 · 2024: 286 · 2023: 355 · 2022: 355 · 2021: 396 · 2020: 388 · 2019: 282 · 2018: 290 · 2017: 273 · 2016: 265 · 2015: 230 · 2014: 243 · 2013: 223 · 2012: 213
FWCI: 56.59
Type: journal article
Language: en
Update notices: erratum (2007-05-17)
Open access: green
doi.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Newcastle University ePrints (Newcastle Univesity)
Funders: 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: PARP inhibitors, BRCA2 deficiency, homologous recombination, synthetic lethality, breast cancer, PARP1, DNA repair, replication fork collapse, single-strand breaks, γH2AX foci, RAD51 foci, base excision repair
MeSH terms: Poly(ADP-ribose) Polymerase Inhibitors, Animals, Antineoplastic Agents, Benzodiazepines, DNA Damage, DNA Repair, DNA Replication, Mice, Nude, Neoplasms, Poly(ADP-ribose) Polymerases, Xenograft Model Antitumor Assays, Genes, BRCA2, BRCA2 Protein, Cell Line, Tumor, Mice, Azulenes

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Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase

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