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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
7
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pubmed:dateCreated |
2011-7-8
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pubmed:abstractText |
Cells that are deficient in homologous recombination, such as those that lack functional breast cancer-associated 1 (BRCA1) or BRCA2, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, BRCA-deficient tumors represent only a small fraction of adult cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. Cyclin-dependent kinase 1 (Cdk1) phosphorylates BRCA1, and this is essential for efficient formation of BRCA1 foci. Here we show that depletion or inhibition of Cdk1 compromises the ability of cells to repair DNA by homologous recombination. Combined inhibition of Cdk1 and PARP in BRCA-wild-type cancer cells resulted in reduced colony formation, delayed growth of human tumor xenografts and tumor regression with prolonged survival in a mouse model of lung adenocarcinoma. Inhibition of Cdk1 did not sensitize nontransformed cells or tissues to inhibition of PARP. Because reduced Cdk1 activity impaired BRCA1 function and consequently, repair by homologous recombination, inhibition of Cdk1 represents a plausible strategy for expanding the utility of PARP inhibitors to BRCA-proficient cancers.
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pubmed:grant |
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/AG 014699,
http://linkedlifedata.com/resource/pubmed/chemical/BRCA1 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Benzimidazoles,
http://linkedlifedata.com/resource/pubmed/chemical/CDC2 Protein Kinase,
http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Indazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Indoles,
http://linkedlifedata.com/resource/pubmed/chemical/N-((5-(3-(4,6-difluoro-1H-benzimidaz...,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Poly(ADP-ribose) Polymerases,
http://linkedlifedata.com/resource/pubmed/chemical/Rad51ap1 protein, mouse
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
1546-170X
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pubmed:author |
pubmed-author:BronsonRoderick TRT,
pubmed-author:ChengKatherine AKA,
pubmed-author:CurtinNicola JNJ,
pubmed-author:D'AndreaAlan DAD,
pubmed-author:JohnsonNeilN,
pubmed-author:LiDananD,
pubmed-author:LiYu-ChenYC,
pubmed-author:MoreauLisa ALA,
pubmed-author:NewellDavid RDR,
pubmed-author:RodigScott JSJ,
pubmed-author:ShapiroGeoffrey IGI,
pubmed-author:ThomasHuw DHD,
pubmed-author:UnittChristineC,
pubmed-author:WaltonZandra EZE,
pubmed-author:WongKwok-KinKK
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pubmed:issnType |
Electronic
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pubmed:volume |
17
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
875-82
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pubmed:dateRevised |
2011-11-10
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pubmed:meshHeading |
pubmed-meshheading:21706030-Animals,
pubmed-meshheading:21706030-BRCA1 Protein,
pubmed-meshheading:21706030-Benzimidazoles,
pubmed-meshheading:21706030-Blotting, Western,
pubmed-meshheading:21706030-Breast Neoplasms,
pubmed-meshheading:21706030-CDC2 Protein Kinase,
pubmed-meshheading:21706030-Carrier Proteins,
pubmed-meshheading:21706030-Cell Death,
pubmed-meshheading:21706030-Cell Line, Tumor,
pubmed-meshheading:21706030-DNA Damage,
pubmed-meshheading:21706030-Female,
pubmed-meshheading:21706030-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:21706030-Humans,
pubmed-meshheading:21706030-Indazoles,
pubmed-meshheading:21706030-Indoles,
pubmed-meshheading:21706030-Male,
pubmed-meshheading:21706030-Mice,
pubmed-meshheading:21706030-Neoplasm Transplantation,
pubmed-meshheading:21706030-Neoplasms, Experimental,
pubmed-meshheading:21706030-Nuclear Proteins,
pubmed-meshheading:21706030-Phosphorylation,
pubmed-meshheading:21706030-Poly(ADP-ribose) Polymerases
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pubmed:year |
2011
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pubmed:articleTitle |
Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition.
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pubmed:affiliation |
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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