title: Molecular Pathways: Targeting ATR in Cancer Therapy.
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.
authors.affiliation: Division of Oncology Research and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota. Karnitz.larry@mayo.edu.
authors.forename: Larry M
authors.initials: LM
authors.lastname: Karnitz
authors.affiliation: Massachusetts General Hospital Cancer Center, Department of Pathology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lee
authors.initials: L
authors.lastname: Zou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D002986:Clinical Trials as Topic; D004249:DNA Damage; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D057170:Translational Research, Biomedical; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1