Cyclin-dependent kinase 2 functions in normal DNA repair and is a therapeutic target in BRCA1-deficient cancers

Andrew J. Deans, Kum Kum Khanna, Carolyn J. McNees, Ciro Mercurio, Jörg Heierhorst, Grant A. McArthur

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)8219-8226
Number of pages8
JournalCancer Research
Volume66
Issue number16
DOIs
Publication statusPublished - Aug 15 2006

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Cyclin-Dependent Kinase 2
DNA Repair
Cyclin-Dependent Kinases
Neoplasms
Neoplasm Genes
Therapeutics
Comet Assay
Homologous Recombination
Cell Cycle Checkpoints
S Phase
Small Interfering RNA
DNA Damage
Cell Cycle
Phosphotransferases
Radiotherapy
Fibroblasts
Drug Therapy
Mutation
DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Deans, A. J., Khanna, K. K., McNees, C. J., Mercurio, C., Heierhorst, J., & McArthur, G. A. (2006). Cyclin-dependent kinase 2 functions in normal DNA repair and is a therapeutic target in BRCA1-deficient cancers. Cancer Research, 66(16), 8219-8226. https://doi.org/10.1158/0008-5472.CAN-05-3945

Cyclin-dependent kinase 2 functions in normal DNA repair and is a therapeutic target in BRCA1-deficient cancers. / Deans, Andrew J.; Khanna, Kum Kum; McNees, Carolyn J.; Mercurio, Ciro; Heierhorst, Jörg; McArthur, Grant A.

In: Cancer Research, Vol. 66, No. 16, 15.08.2006, p. 8219-8226.

Research output: Contribution to journalArticle

Deans, AJ, Khanna, KK, McNees, CJ, Mercurio, C, Heierhorst, J & McArthur, GA 2006, 'Cyclin-dependent kinase 2 functions in normal DNA repair and is a therapeutic target in BRCA1-deficient cancers', Cancer Research, vol. 66, no. 16, pp. 8219-8226. https://doi.org/10.1158/0008-5472.CAN-05-3945
Deans, Andrew J. ; Khanna, Kum Kum ; McNees, Carolyn J. ; Mercurio, Ciro ; Heierhorst, Jörg ; McArthur, Grant A. / Cyclin-dependent kinase 2 functions in normal DNA repair and is a therapeutic target in BRCA1-deficient cancers. In: Cancer Research. 2006 ; Vol. 66, No. 16. pp. 8219-8226.
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