title: ATM and ATR as therapeutic targets in cancer.
abstract: In order to maintain genomic stability, cells have developed sophisticated signalling pathways to enable DNA damage or DNA replication stress to be resolved. Key mediators of this DNA damage response (DDR) are the ATM and ATR kinases, which induce cell cycle arrest and facilitate DNA repair via their downstream targets. Inhibiting the DDR has become an attractive therapeutic concept in cancer therapy, since (i) resistance to genotoxic therapies has been associated with increased DDR signalling, and (ii) many cancers have defects in certain components of the DDR rendering them highly dependent on the remaining DDR pathways for survival. ATM and ATR act as the apical regulators of the response to DNA double strand breaks and replication stress, respectively, with overlapping but non-redundant activities. Highly selective small molecule inhibitors of ATM and ATR are currently in preclinical and clinical development, respectively. Preclinical data have provided a strong rationale for clinical testing of these compounds both in combination with radio- or chemotherapy, and in synthetic lethal approaches to treat tumours with deficiencies in certain DDR components. Whole genome sequencing studies have reported that mutations in DDR genes occur with a high frequency in many common tumour types, suggesting that a synthetic lethal approach with ATM or ATR inhibitors could have widespread utility, providing that appropriate biomarkers are developed.
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, The Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Anika Maria
authors.initials: AM
authors.lastname: Weber
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, The Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK. Electronic address: anderson.ryan@oncology.ox.ac.uk.
authors.forename: Anderson Joseph
authors.initials: AJ
authors.lastname: Ryan
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D018579:Patient Selection; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases
keywords: ATM; ATR; DNA damage response; Synthetic lethality