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 language | English |
|---|---|
| Pages (from-to) | 8219-8226 |
| Number of pages | 8 |
| Journal | Cancer Research |
| Volume | 66 |
| Issue number | 16 |
| DOIs | |
| Publication status | Published - Aug 15 2006 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Cyclin-dependent kinase 2 functions in normal DNA repair and is a therapeutic target in BRCA1-deficient cancers
AU - Deans, Andrew J.
AU - Khanna, Kum Kum
AU - McNees, Carolyn J.
AU - Mercurio, Ciro
AU - Heierhorst, Jörg
AU - McArthur, Grant A.
PY - 2006/8/15
Y1 - 2006/8/15
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=33748069123&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-05-3945
DO - 10.1158/0008-5472.CAN-05-3945
M3 - Article
C2 - 16912201
AN - SCOPUS:33748069123
VL - 66
SP - 8219
EP - 8226
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 16
ER -