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Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition

Lookup NU author(s): Huw ThomasORCiD, Professor Herbie Newell, Professor Nicola CurtinORCiD

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Abstract

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. Cyclindependent 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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Author(s): Johnson N, Li YC, Walton ZE, Cheng KA, Li DA, Rodig SJ, Moreau LA, Unitt C, Bronson RT, Thomas HD, Newell DR, D'Andrea AD, Curtin NJ, Wong KK, Shapiro GI

Publication type: Article

Publication status: Published

Journal: Nature Medicine

Year: 2011

Volume: 17

Issue: 7

Pages: 875-882

Print publication date: 26/06/2011

ISSN (print): 1078-8956

ISSN (electronic): 1546-170X

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/nm.2377

DOI: 10.1038/nm.2377

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