Document Detail

Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations.
MedLine Citation:
PMID:  21487248     Owner:  NLM     Status:  MEDLINE    
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.
Konstantin J Dedes; Paul M Wilkerson; Daniel Wetterskog; Britta Weigelt; Alan Ashworth; Jorge S Reis-Filho
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-04-15
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  10     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-04-22     Completed Date:  2011-08-31     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1192-9     Citation Subset:  IM    
The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
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MeSH Terms
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
Gene Expression
Germ-Line Mutation
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
//Cancer Research UK; //Wellcome Trust
Reg. No./Substance:
0/Antineoplastic Agents; 0/BRCA1 Protein; 0/BRCA2 Protein; 0/Enzyme Inhibitors; EC Polymerases

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