title: Anticancer therapy with checkpoint inhibitors: what, where and when?
abstract: Research into inhibitors of the protein kinases controlling the cellular response to DNA damage has reached an exciting stage, particularly for the checkpoint kinases CHK1 and CHK2. Selective inhibitors are now being tested in clinical trials in cancer patients. In this review, we highlight recent data from cellular and in vivo preclinical models that provide insight into the clinical contexts for checkpoint kinase inhibition (e.g. the timing of treatment and what type of inhibitor would be most appropriate). Although it has been shown that CHK1 inhibition potentiates the efficacy of various DNA-damaging therapies, the context for selective CHK2 inhibition is not yet as well defined. Distinct effects of selective CHK1 or CHK2 inhibition are observed when combined with DNA-damaging agents. It has also been shown that both CHK1 and CHK2 inhibitors potentiate the effects of other molecular targeted therapeutics [e.g. poly(ADP-ribose) polymerase inhibitors]. We also consider the single-agent activity of checkpoint kinase inhibitors for tumours with defined genetic backgrounds.
authors: Cancer Research UK Cancer Therapeutics Unit, Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton SM25NG, UK.
authors: Michelle D
authors: MD
authors: Garrett
authors: Ian
authors: I
authors: Collins
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000187:drug effects; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases