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Cyclin-Dependent Kinase 2 Functions in Normal DNA Repair and Is a Therapeutic Target in BRCA1-Deficient Cancers

¹ Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; ² Queensland Institute of Medical Research, Herston, Queensland, Australia; ³ St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia; ⁴ Nerviano Medical Sciences, BU-Oncology and BU-Preclinical Science, Milan, Italy; and ⁵ Department of Medicine, St Vincent's Hospital, The University of Melbourne, Parkville, Victoria, Australia

Requests for reprints: Grant A. McArthur, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, Melbourne, Victoria 8006, Australia. Phone: 61-3-9656-1195; Fax: 61-3-9656-1411; E-mail: grant.mcarthur{at}petermac.org.

Abnormal regulation of progression from G₁ to S phase of the cell cycle by altered activity of cyclin-dependent kinases (CDKs) is a hallmark of cancer. However, inhibition of CDKs, particularly CDK2, has not shown selective activity against most cancer cells because the kinase seems to be redundant in control of cell cycle progression. Here, we show a novel role in the DNA damage response and application of CDK inhibitors in checkpoint-deficient cells. CDK2^–/– mouse fibroblasts and small interfering RNA–mediated or small-molecule–mediated CDK2 inhibition in MCF7 or U2OS cells lead to delayed damage signaling through Chk1, p53, and Rad51. This coincided with reduced DNA repair using the single-cell comet assay and defects observed in both homologous recombination and nonhomologous end-joining in cell-based assays. Furthermore, tumor cells lacking cancer predisposition genes BRCA1 or ATM are 2- to 4-fold more sensitive to CDK inhibitors. These data suggest that inhibitors of CDK2 can be applied to selectively enhance responses of cancer cells to DNA-damaging agents, such as cytotoxic chemotherapy and radiotherapy. Moreover, inhibitors of CDKs may be useful therapeutics in cancers with defects in DNA repair, such as mutations in the familial breast cancer gene BRCA1. (Cancer Res 2006; 66(16): 8219-26)

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