title: Targeting ATR in DNA damage response and cancer therapeutics.
abstract: The ataxia telangiectasia and Rad3-related (ATR) plays an important role in maintaining genome integrity during DNA replication through the phosphorylation and activation of Chk1 and regulation of the DNA damage response. Preclinical studies have shown that disruption of ATR pathway can exacerbate the levels of replication stress in oncogene-driven murine tumors to promote cell killing. Additionally, inhibition of ATR can sensitise tumor cells to radiation or chemotherapy. Accumulating evidence suggests that targeting ATR can selectively sensitize cancer cells but not normal cells to DNA damage. Furthermore, in hypoxic conditions, ATR blockade results in overloading replication stress and DNA damage response causing cell death. Despite the attractiveness of ATR inhibition in the treatment of cancer, specific ATR inhibitors have remained elusive. In the last two years however, selective ATR inhibitors suitable for in vitro and - most recently - in vivo studies have been identified. In this article, we will review the literature on ATR function, its role in DDR and the potential of ATR inhibition to enhance the efficacy of radiation and chemotherapy.
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, Oxford University, Oxford, United Kingdom; Department of Radiation Therapy and Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany. Electronic address: emmanouil.fokas@kgu.de.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Fokas
authors.forename: Remko
authors.initials: R
authors.lastname: Prevo
authors.forename: Ester M
authors.initials: EM
authors.lastname: Hammond
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Brunner
authors.forename: W Gillies
authors.initials: WG
authors.lastname: McKenna
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Muschel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D004249:DNA Damage; D004261:DNA Replication; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction
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
keywords: ATR; Cancer; Chemotherapy; DNA damage; Radiation; Replication stress; Therapeutics