COMPROMISED CDK1 ACTIVITY SENSITIZES BRCA-PROFICIENT CANCERS TO PARP INHIBITION

Homologous recombination (HR)-defective cells, such as those lacking BRCA1/2, are hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibition. However, BRCA-deficient tumors represent only a small fraction of adult cancers, potentially restricting the therapeutic utility of PARP inhibitor monot...

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Main Authors:	Johnson, Neil, Li, Yu-Chen, Walton, Zandra E., Cheng, Katherine A., Li, Danan, Rodig, Scott J., Moreau, Lisa A., Unitt, Christine, Bronson, Roderick T., Thomas, Huw D., Newell, David R., D’Andrea, Alan D., Curtin, Nicola J., Wong, Kwok-Kin, Shapiro, Geoffrey I.
Format:	Online
Language:	English
Published:	2011
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272302/

id	pubmed-3272302
recordtype	oai_dc
spelling	pubmed-32723022012-02-04 COMPROMISED CDK1 ACTIVITY SENSITIZES BRCA-PROFICIENT CANCERS TO PARP INHIBITION Johnson, Neil Li, Yu-Chen Walton, Zandra E. Cheng, Katherine A. Li, Danan Rodig, Scott J. Moreau, Lisa A. Unitt, Christine Bronson, Roderick T. Thomas, Huw D. Newell, David R. D’Andrea, Alan D. Curtin, Nicola J. Wong, Kwok-Kin Shapiro, Geoffrey I. Article Homologous recombination (HR)-defective cells, such as those lacking BRCA1/2, are hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibition. However, BRCA-deficient tumors represent only a small fraction of adult cancers, potentially restricting the therapeutic utility of PARP inhibitor monotherapy. We previously showed that cyclin-dependent kinase (cdk)1 phosphorylates BRCA1, an event essential for efficient BRCA1 focus formation. Here, we show that cdk1 depletion or inhibition compromises the cellular capacity to repair DNA by HR. Combined cdk1 and PARP inhibition in BRCA wild-type cancer cells results in reduced colony formation, delayed human tumor xenograft growth and tumor regression with prolonged survival in a mouse lung adenocarcinoma model. Cdk1 inhibition did not sensitize non-transformed cells or tissues to PARP inhibition. Because reduced cdk1 activity impairs BRCA1 function and HR repair, cdk1 inhibition represents a plausible strategy for expanding the utility of PARP inhibitors to the BRCA-proficient cancer population. 2011-06-26 /pmc/articles/PMC3272302/ /pubmed/21706030 http://dx.doi.org/10.1038/nm.2377 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Johnson, Neil Li, Yu-Chen Walton, Zandra E. Cheng, Katherine A. Li, Danan Rodig, Scott J. Moreau, Lisa A. Unitt, Christine Bronson, Roderick T. Thomas, Huw D. Newell, David R. D’Andrea, Alan D. Curtin, Nicola J. Wong, Kwok-Kin Shapiro, Geoffrey I.
spellingShingle	Johnson, Neil Li, Yu-Chen Walton, Zandra E. Cheng, Katherine A. Li, Danan Rodig, Scott J. Moreau, Lisa A. Unitt, Christine Bronson, Roderick T. Thomas, Huw D. Newell, David R. D’Andrea, Alan D. Curtin, Nicola J. Wong, Kwok-Kin Shapiro, Geoffrey I. COMPROMISED CDK1 ACTIVITY SENSITIZES BRCA-PROFICIENT CANCERS TO PARP INHIBITION
author_facet	Johnson, Neil Li, Yu-Chen Walton, Zandra E. Cheng, Katherine A. Li, Danan Rodig, Scott J. Moreau, Lisa A. Unitt, Christine Bronson, Roderick T. Thomas, Huw D. Newell, David R. D’Andrea, Alan D. Curtin, Nicola J. Wong, Kwok-Kin Shapiro, Geoffrey I.
author_sort	Johnson, Neil
title	COMPROMISED CDK1 ACTIVITY SENSITIZES BRCA-PROFICIENT CANCERS TO PARP INHIBITION
title_short	COMPROMISED CDK1 ACTIVITY SENSITIZES BRCA-PROFICIENT CANCERS TO PARP INHIBITION
title_full	COMPROMISED CDK1 ACTIVITY SENSITIZES BRCA-PROFICIENT CANCERS TO PARP INHIBITION
title_fullStr	COMPROMISED CDK1 ACTIVITY SENSITIZES BRCA-PROFICIENT CANCERS TO PARP INHIBITION
title_full_unstemmed	COMPROMISED CDK1 ACTIVITY SENSITIZES BRCA-PROFICIENT CANCERS TO PARP INHIBITION
title_sort	compromised cdk1 activity sensitizes brca-proficient cancers to parp inhibition
description	Homologous recombination (HR)-defective cells, such as those lacking BRCA1/2, are hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibition. However, BRCA-deficient tumors represent only a small fraction of adult cancers, potentially restricting the therapeutic utility of PARP inhibitor monotherapy. We previously showed that cyclin-dependent kinase (cdk)1 phosphorylates BRCA1, an event essential for efficient BRCA1 focus formation. Here, we show that cdk1 depletion or inhibition compromises the cellular capacity to repair DNA by HR. Combined cdk1 and PARP inhibition in BRCA wild-type cancer cells results in reduced colony formation, delayed human tumor xenograft growth and tumor regression with prolonged survival in a mouse lung adenocarcinoma model. Cdk1 inhibition did not sensitize non-transformed cells or tissues to PARP inhibition. Because reduced cdk1 activity impairs BRCA1 function and HR repair, cdk1 inhibition represents a plausible strategy for expanding the utility of PARP inhibitors to the BRCA-proficient cancer population.
publishDate	2011
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272302/
_version_	1611503774764892160

COMPROMISED CDK1 ACTIVITY SENSITIZES BRCA-PROFICIENT CANCERS TO PARP INHIBITION

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