Abstract
Abnormal regulation of progression from G(1) 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.
Highlights
The DNA damage response in mammalian cells is an evolutionarily conserved pathway that protects cells from the lethal or tumor-promoting consequences of genotoxic insult
We provide evidence that these drugs may be useful in treating cancers that are deficient in familial breast cancer genes BRCA1 and ATM based on a novel role for cyclin-dependent kinase 2 (CDK2) in the DNA damage response
CDK2 was originally thought to play an essential role in the initiation of DNA synthesis in S phase, CDK2 small interfering RNA (siRNA) in human cancer cells or targeted deletion in the mouse is nondeleterious and CDK2À/À somatic cells continue to cycle www.aacrjournals.org normally [25, 26]
Summary
The DNA damage response in mammalian cells is an evolutionarily conserved pathway that protects cells from the lethal or tumor-promoting consequences of genotoxic insult. Mutation in DNA repair genes, such as BRCA1, BRCA2, and ATM, accounts for a significant proportion of the breast cancers attributed to a familial predisposition, highlighting the importance of this process in tumor protection. Cell cycle regulation is thought to be important in regulating the DNA repair process. Nonhomologous end-joining (NHEJ) and homologous recombination (HR) are differently regulated in cycling versus quiescent cells, and the overall rate of DNA repair is faster in cells that are rapidly cycling compared with those that are quiescent [1]. We propose a candidate and therapeutic target in this temporal regulation, cyclin-dependent kinase 2 (CDK2). Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/)
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