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Molecular Pathways: Targeting ATR in Cancer Therapy.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2015 Nov 01; Vol. 21 (21), pp. 4780-5. Date of Electronic Publication: 2015 Sep 11. - Publication Year :
- 2015
-
Abstract
- The human ATR gene encodes a kinase that is activated by DNA damage and replication stress as a central transducer of a checkpoint signaling pathway. Once activated, ATR phosphorylates multiple substrates, including the kinase Chk1, to regulate cell-cycle progression, replication fork stability, and DNA repair. These events promote cell survival during replication stress and in cells with DNA damage. Accordingly, there has been the tantalizing possibility that ATR inhibitors would be therapeutically useful, especially if they were more effective in tumor versus normal cells. Indeed, multiple studies have demonstrated that alterations that promote tumorigenesis, such as defects in the ATM-p53 pathway, constitutive oncogene activation, and acquisition of the alternative lengthening of telomeres pathway, render tumor cells sensitive to ATR inhibitor monotherapy and/or increase the synergy between ATR inhibitors and genotoxic chemotherapies. Now, nearly two decades after the discovery of ATR, two highly selective and potent ATR inhibitors, AZD6738 and VX-970, are in early-phase clinical trials either as monotherapies or paired with a variety of genotoxic chemotherapies. These trials will generate important insights into the effects of ATR inhibition in humans and the potential role of inhibiting this kinase in the treatment of human malignancies.<br /> (©2015 American Association for Cancer Research.)
- Subjects :
- Animals
Antineoplastic Agents pharmacology
Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors
Ataxia Telangiectasia Mutated Proteins genetics
Ataxia Telangiectasia Mutated Proteins metabolism
Checkpoint Kinase 1
Clinical Trials as Topic
DNA Damage
Humans
Neoplasms etiology
Protein Kinase Inhibitors pharmacology
Protein Kinases metabolism
Translational Research, Biomedical
Treatment Outcome
Antineoplastic Agents therapeutic use
Molecular Targeted Therapy
Neoplasms drug therapy
Neoplasms metabolism
Protein Kinase Inhibitors therapeutic use
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 21
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 26362996
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-15-0479