Targeting DNA Checkpoint Kinases in Cancer Therapy

The DNA damage response includes not only cell cycle arrest and apoptosis, but also direct activation of DNA repair networks. Four DNA checkpoint kinases ATM, ATR, Chk1 and Chk2 have been identified in the mammalian DNA damage response signal transduction pathway. In this article, we review and discuss current knowledge and thinking about checkpoint kinases, and their potential as cancer drug targets. Particular emphasis is given to various therapeutic hypotheses and their promise for improving current cancer therapies.

[1]  Jiri Bartek,et al.  Regulation of G2/M events by Cdc25A through phosphorylation‐dependent modulation of its stability , 2002, The EMBO journal.

[2]  Hui Zhao,et al.  Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[3]  E. Appella,et al.  Chk2‐deficient mice exhibit radioresistance and defective p53‐mediated transcription , 2002, The EMBO journal.

[4]  Michael J Bower,et al.  Structural basis for Chk1 inhibition by UCN-01. , 2002, The Journal of biological chemistry.

[5]  S. Jackson,et al.  Interfaces Between the Detection, Signaling, and Repair of DNA Damage , 2002, Science.

[6]  L. Iyer,et al.  Determination of Substrate Motifs for Human Chk1 and hCds1/Chk2 by the Oriented Peptide Library Approach* , 2002, The Journal of Biological Chemistry.

[7]  S. Jackson,et al.  The MRE11 complex: at the crossroads of DNA repair and checkpoint signalling , 2002, Nature Reviews Molecular Cell Biology.

[8]  Nazneen Rahman,et al.  Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations , 2002, Nature Genetics.

[9]  M. Kastan,et al.  Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage. , 2002, Genes & development.

[10]  Jun Qin,et al.  SMC1 is a downstream effector in the ATM/NBS1 branch of the human S-phase checkpoint. , 2002, Genes & development.

[11]  J. Bartek,et al.  The DNA damage-dependent intra–S phase checkpoint is regulated by parallel pathways , 2002, Nature Genetics.

[12]  Scott W. Lowe,et al.  Apoptosis A Link between Cancer Genetics and Chemotherapy , 2002, Cell.

[13]  Jun Qin,et al.  ATR and ATRIP: Partners in Checkpoint Signaling , 2001, Science.

[14]  A. Cuddihy,et al.  Inhibition of Chk1-dependent G2 DNA damage checkpoint radiosensitizes p53 mutant human cells , 2001, Oncogene.

[15]  S. Schwartz,et al.  Somatic mutations in the DNA damage-response genes ATR and CHK1 in sporadic stomach tumors with microsatellite instability. , 2001, Cancer research.

[16]  R. Abraham.  Cell cycle checkpoint signaling through the ATM and ATR kinases. , 2001, Genes & development.

[17]  R. Stein.  Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment. , 2001, Endocrine-related cancer.

[18]  L. Aaltonen,et al.  p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. , 2001, Cancer research.

[19]  J. Nevins,et al.  Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation. , 2001, Genes & development.

[20]  H. Piwnica-Worms,et al.  ATR-Mediated Checkpoint Pathways Regulate Phosphorylation and Activation of Human Chk1 , 2001, Molecular and Cellular Biology.

[21]  N. Mailand,et al.  DNA damage-activated kinase Chk2 is independent of proliferation or differentiation yet correlates with tissue biology. , 2001, Cancer research.

[22]  David E. Williams,et al.  Inhibition of the G2 DNA Damage Checkpoint and of Protein Kinases Chk1 and Chk2 by the Marine Sponge Alkaloid Debromohymenialdisine* , 2001, The Journal of Biological Chemistry.

[23]  E. Sausville,et al.  Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  N. Mailand,et al.  The ATM–Chk2–Cdc25A checkpoint pathway guards against radioresistant DNA synthesis , 2001, Nature.

[25]  W. Hofmann,et al.  Mutation analysis of the DNA-damage checkpoint gene CHK2 in myelodysplastic syndromes and acute myeloid leukemias. , 2001, Leukemia research.

[26]  K. Khanna,et al.  DNA double-strand breaks: signaling, repair and the cancer connection , 2001, Nature Genetics.

[27]  K. Cimprich,et al.  Xenopus ATR is a replication-dependent chromatin-binding protein required for the DNA replication checkpoint , 2000, Current Biology.

[28]  S. Elledge,et al.  Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. , 2000, Genes & development.

[29]  S. Elledge,et al.  The DNA damage response: putting checkpoints in perspective , 2000, Nature.

[30]  H. Piwnica-Worms,et al.  Threonine 68 phosphorylation by ataxia telangiectasia mutated is required for efficient activation of Chk2 in response to ionizing radiation. , 2000, Cancer research.

[31]  A. Blasina,et al.  Threonine 68 is required for radiation-induced phosphorylation and activation of Cds1 , 2000, Nature Cell Biology.

[32]  E. Fanning,et al.  Activation of the DNA replication checkpoint through RNA synthesis by primase. , 2000, Science.

[33]  H. Konishi,et al.  Histological type-selective, tumor-predominant expression of a novel CHK1 isoform and infrequent in vivo somatic CHK2 mutation in small cell lung cancer. , 2000, Cancer research.

[34]  D. Chan,et al.  Utilization of Oriented Peptide Libraries to Identify Substrate Motifs Selected by ATM* , 2000, The Journal of Biological Chemistry.

[35]  Y. A. Minamishima,et al.  Aberrant cell cycle checkpoint function and early embryonic death in Chk1(-/-) mice. , 2000, Genes & development.

[36]  S. Elledge,et al.  Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. , 2000, Genes & development.

[37]  N. Mailand,et al.  Rapid destruction of human Cdc25A in response to DNA damage. , 2000, Science.

[38]  E. Sausville,et al.  UCN-01 Enhances the In Vitro Toxicity of Clinical Agents in Human Tumor Cell Lines , 2000, Investigational New Drugs.

[39]  J. Sarkaria,et al.  The radiosensitizing agent 7-hydroxystaurosporine (UCN-01) inhibits the DNA damage checkpoint kinase hChk1. , 2000, Cancer research.

[40]  A. Carr,et al.  Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice , 2000, Current Biology.

[41]  K. Khanna,et al.  Caffeine Abolishes the Mammalian G2/M DNA Damage Checkpoint by Inhibiting Ataxia-Telangiectasia-mutated Kinase Activity* , 2000, The Journal of Biological Chemistry.

[42]  P. May,et al.  Cell cycle control and cancer. , 2000, Pathologie-biologie.

[43]  S. Elledge,et al.  DNA damage-induced activation of p53 by the checkpoint kinase Chk2. , 2000, Science.

[44]  Jong-Soo Lee,et al.  hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response , 2000, Nature.

[45]  Edward A. Sausville,et al.  The Chk1 Protein Kinase and the Cdc25C Regulatory Pathways Are Targets of the Anticancer Agent UCN-01* , 2000, The Journal of Biological Chemistry.

[46]  D. Baltimore,et al.  ATR disruption leads to chromosomal fragmentation and early embryonic lethality. , 2000, Genes & development.

[47]  J. Jackson,et al.  An indolocarbazole inhibitor of human checkpoint kinase (Chk1) abrogates cell cycle arrest caused by DNA damage. , 2000, Cancer research.

[48]  T. Halazonetis,et al.  Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. , 2000, Genes & development.

[49]  Y Taya,et al.  The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. , 2000, Genes & development.

[50]  S. T. Kim,et al.  Substrate Specificities and Identification of Putative Substrates of ATM Kinase Family Members* , 1999, The Journal of Biological Chemistry.

[51]  K. Isselbacher,et al.  Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. , 1999, Science.

[52]  E. Stavridi,et al.  Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[53]  C. Smythe,et al.  ATR is a caffeine-sensitive, DNA-activated protein kinase with a substrate specificity distinct from DNA-PK , 1999, Oncogene.

[54]  B. Koller,et al.  Brca1 controls homology-directed DNA repair. , 1999, Molecular cell.

[55]  M V Chernov,et al.  A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. , 1999, Science.

[56]  J. Sarkaria,et al.  Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. , 1999, Cancer research.

[57]  S. Carr,et al.  Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway , 1999, Oncogene.

[58]  M. Nakanishi,et al.  Cell cycle-dependent and ATM-independent expression of human Chk1 kinase , 1999, Oncogene.

[59]  H. Piwnica-Worms,et al.  A human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[60]  D. Broccoli,et al.  p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. , 1999, Science.

[61]  R. Wells,et al.  Wortmannin sensitizes mammalian cells to radiation by inhibiting the DNA-dependent protein kinase-mediated rejoining of double-strand breaks. , 1999, Radiation research.

[62]  A. Blasina,et al.  A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase , 1999, Current Biology.

[63]  P. Leder,et al.  Loss of atm radiosensitizes multiple p53 null tissues. , 1998, Cancer research.

[64]  S. Elledge,et al.  Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. , 1998, Science.

[65]  E. Sausville,et al.  Unpredicted clinical pharmacology of UCN-01 caused by specific binding to human alpha1-acid glycoprotein. , 1998, Cancer research.

[66]  L. Goodrich,et al.  Duplication of ATR inhibits MyoD, induces aneuploidy and eliminates radiation-induced G1 arrest , 1998, Nature Genetics.

[67]  M. Urano,et al.  The effect of UCN-01 (7-hydroxystaurosporine), a potent inhibitor of protein kinase C, on fractionated radiotherapy or daily chemotherapy of a murine fibrosarcoma. , 1997, International journal of radiation oncology, biology, physics.

[68]  K. Kohn,et al.  Abrogation of an S-phase checkpoint and potentiation of camptothecin cytotoxicity by 7-hydroxystaurosporine (UCN-01) in human cancer cell lines, possibly influenced by p53 function. , 1997, Cancer research.

[69]  C. Peng,et al.  Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. , 1997, Science.

[70]  S. Elledge,et al.  Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. , 1997, Science.

[71]  P. Leder,et al.  atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity , 1997, Nature Genetics.

[72]  A. Levine.  p53, the Cellular Gatekeeper for Growth and Division , 1997, Cell.

[73]  P. Leder,et al.  Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[74]  D. Baltimore,et al.  Dual roles of ATM in the cellular response to radiation and in cell growth control. , 1996, Genes & development.

[75]  D. Baltimore,et al.  Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. , 1996, Genes & development.

[76]  E. Sausville,et al.  UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53. , 1996, Journal of the National Cancer Institute.

[77]  Francis Collins,et al.  Atm-Deficient Mice: A Paradigm of Ataxia Telangiectasia , 1996, Cell.

[78]  A. Eastman,et al.  Enhancement of cisplatin-induced cytotoxicity by 7-hydroxystaurosporine (UCN-01), a new G2-checkpoint inhibitor. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[79]  M. Lovett,et al.  A single ataxia telangiectasia gene with a product similar to PI-3 kinase. , 1995, Science.

[80]  S. Friend,et al.  Differential sensitivity of p53(-) and p53(+) cells to caffeine-induced radiosensitization and override of G2 delay. , 1995, Cancer research.

[81]  M. Groudine,et al.  Abrogation of the G2 checkpoint results in differential radiosensitization of G1 checkpoint-deficient and G1 checkpoint-competent cells. , 1995, Cancer research.

[82]  K. Kohn,et al.  Disruption of p53 function sensitizes breast cancer MCF-7 cells to cisplatin and pentoxifylline. , 1995, Cancer research.

[83]  E. Sausville,et al.  Differential inhibition of protein kinase C isozymes by UCN-01, a staurosporine analogue. , 1994, Molecular pharmacology.

[84]  S. Akinaga,et al.  Antitumor activity of UCN-01, a selective inhibitor of protein kinase C, in murine and human tumor models. , 1991, Cancer research.

[85]  L. Hartwell,et al.  Checkpoints: controls that ensure the order of cell cycle events. , 1989, Science.

[86]  L. Hartwell,et al.  The RAD9 gene controls the cell cycle response to DNA damage in Saccharomyces cerevisiae. , 1988, Science.

[87]  J. Maroun,et al.  Cytosine arabinoside plus cisplatin and other drugs as chemotherapy for gliomas. , 1987, Seminars in oncology.

[88]  R. Tobey.  Different drugs arrest cells at a number of distinct stages in G2 , 1975, Nature.

[89]  S. Akinaga,et al.  Enhancement of antitumor activity of mitomycin C in vitro and in vivo by UCN-01, a selective inhibitor of protein kinase C , 2004, Cancer Chemotherapy and Pharmacology.

[90]  M. Gatei,et al.  Ataxia Telangiectasia Mutated (ATM) Kinase and ATM and Rad3 Related Kinase Mediate Phosphorylation of Brca1 at Distinct and Overlapping Sites IN VIVO ASSESSMENT USING PHOSPHO-SPECIFIC ANTIBODIES* , 2001 .

[91]  Y. Shiloh,et al.  ATM: genome stability, neuronal development, and cancer cross paths. , 2001, Advances in cancer research.

[92]  K. Khanna,et al.  ATM: the protein encoded by the gene mutated in the radiosensitive syndrome ataxia-telangiectasia. , 1999, International journal of radiation biology.

[93]  S. Schreiber,et al.  Overexpression of a kinase‐inactive ATR protein causes sensitivity to DNA‐damaging agents and defects in cell cycle checkpoints , 1998, The EMBO journal.