| Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations. | |
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MedLine Citation:
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PMID: 21487248 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Utilizing the concept of synthetic lethality has provided new opportunities for the development of targeted therapies, by allowing the targeting of loss of function genetic aberrations. In cancer cells with BRCA1 or BRCA2 loss of function, which harbor deficiency of DNA repair by homologous recombination, inhibition of PARP1 enzymatic activity leads to an accumulation of single strand breaks that are converted to double strand breaks but cannot be repaired by homologous recombination. Inhibition of PARP has therefore been advanced as a novel targeted therapy for cancers harboring BRCA1/2 mutations. Preclinical and preliminary clinical evidence, however, suggests a potentially broader scope for PARP inhibitors. Loss of function of various proteins involved in double strand break repair other than BRCA1/2 has been suggested to be synthetically lethal with PARP inhibition. Inactivation of these genes has been reported in a subset of human cancers and might therefore constitute predictive biomarkers for PARP inhibition. Here we discuss the evidence that the clinical use of PARP inhibition may be broader than targeting of cancers in BRCA1/2 germ-line mutation carriers. |
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Authors:
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Konstantin J Dedes; Paul M Wilkerson; Daniel Wetterskog; Britta Weigelt; Alan Ashworth; Jorge S Reis-Filho |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-04-15 |
Journal Detail:
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Title: Cell cycle (Georgetown, Tex.) Volume: 10 ISSN: 1551-4005 ISO Abbreviation: Cell Cycle Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-04-22 Completed Date: 2011-08-31 Revised Date: 2012-09-20 |
Medline Journal Info:
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Nlm Unique ID: 101137841 Medline TA: Cell Cycle Country: United States |
Other Details:
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Languages: eng Pagination: 1192-9 Citation Subset: IM |
Affiliation:
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The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antineoplastic Agents / pharmacology, therapeutic use BRCA1 Protein / deficiency*, genetics BRCA2 Protein / deficiency*, genetics Clinical Trials as Topic DNA Methylation / drug effects DNA Repair / drug effects* Disease Models, Animal Enzyme Inhibitors / pharmacology, therapeutic use Epistasis, Genetic Female Gene Expression Germ-Line Mutation Humans Male Mice Mice, Knockout Molecular Targeted Therapy / methods Neoplasms / drug therapy, genetics*, pathology Poly(ADP-ribose) Polymerases / antagonists & inhibitors*, genetics, metabolism Recombination, Genetic* / drug effects |
| Grant Support | |
ID/Acronym/Agency:
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//Cancer Research UK; //Wellcome Trust |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/BRCA1 Protein; 0/BRCA2 Protein; 0/Enzyme Inhibitors; EC 2.4.2.30/Poly(ADP-ribose) Polymerases |
| Comments/Corrections | |
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