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

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

doi:10.1038/nature03445

Cited by 5,738 publications

(4,737 citation statements)

References 22 publications

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“…Molecules targeting DNA repair have been developed and are used in the clinic to treat cancers,39, 40 and such therapeutics, along with others in development, may prove useful in some or all of the polyglutamine diseases. Furthermore, these shared mechanisms may extend to diseases associated with non‐CAG and nontranslated repeats, most likely in those that show somatic instability.…”

Section: Discussionmentioning

confidence: 99%

DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

Bettencourt

Hensman-Moss

Flower

et al. 2016

Annals of Neurology

197

186

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ObjectiveThe polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome‐wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases.MethodsWe assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single‐nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study.ResultsIn the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10–5) and all SCAs (p = 2.22 × 10–4) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10–5), all in the same direction as in the HD GWAS.InterpretationWe show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016;79:983–990

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Section: Discussionmentioning

confidence: 99%

DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

Bettencourt

Hensman-Moss

Flower

et al. 2016

Annals of Neurology

197

186

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“…This radiosensitization may result from PARP-mediated Targeting DDR pathways to improve cancer treatment F Al-Ejeh et al inhibition of single-strand break repair at stalled replication forks leading to the creation of DSBs (Haince et al, 2005). Consequently, up to 1000-fold higher sensitivity of BRCA-deficient (Bryant et al, 2005;Farmer et al, 2005;McCabe et al, 2005McCabe et al, , 2006Evers et al, 2008) or FA protein-deficient cells to PARP inhibition seems to depend on the excess of DSBs generated in the presence of compromised HR. Increased G2/M arrest upon PARP inhibition could explain the higher growth inhibition in FA proteindeficient cells .…”

Section: Arrest/senescencementioning

confidence: 99%

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

et al. 2010

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“…The inhibition of PARPs potentiates the activity of DNA-damaging agents such as alkylators, platinums, topoisomerase inhibitors and radiation in in vitro and in vivo models (Tentori and Graziani, 2005;Plummer and Calvert, 2007). In addition, tumors with DNA repair defects, such as those arising from patients with BRCA mutations, are more sensitive to PARP inhibition, suggesting that PARP inhibitors may be particularly useful for the treatment of cancer with BRCA mutations (Farmer et al, 2005). On the basis of the promising data on preclinical models, different companies have now initiated oncology clinical trials with PARP inhibitors, ranging in stages from phase 0 to phase 2 (Ratnam and Low, 2007).…”

Section: Introductionmentioning

confidence: 99%

PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy

Salvati¹,

Scarsella²,

Porru³

et al. 2010

Oncogene

108

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New anti-telomere strategies represent important goals for the development of selective cancer therapies. In this study, we reported that uncapped telomeres, resulting from pharmacological stabilization of quadruplex DNA by RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino [4,3,2-kl]acridinium methosulfate), trigger specific recruitment and activation of poly-adenosine diphosphate (ADP) ribose polymerase I (PARP1) at the telomeres, forming several ADP-ribose polymers that co-localize with the telomeric repeat binding factor 1 protein and are inhibited by selective PARP(s) inhibitors or PARP1-specific small interfering RNAs. The knockdown of PARP1 prevents repairing of RHPS4-induced telomere DNA breaks, leading to increases in chromosome abnormalities and eventually to the inhibition of tumor cell growth both in vitro and in xenografts. More interestingly, the integration of a TOPO1 inhibitor on the combination treatment proved to have a high therapeutic efficacy ensuing a complete regression of the tumor as well as a significant increase in overall survival and cure of mice even when treatments started at a very late stage of tumor growth. Overall, this work reveals the unexplored link between the PARP1 and G-quadruplex ligands and demonstrates the excellent efficacy of a multicomponent strategy based on the use of PARP inhibitors in telomere-based therapy.

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

Cited by 5,738 publications

References 22 publications

DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy

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