title: CHK1 inhibitors in combination chemotherapy: thinking beyond the cell cycle.
abstract: Cellular sensing of DNA damage, along with concomitant cell cycle arrest, is mediated by a great many proteins and enzymes. One focus of pharmaceutical development has been the inhibition of DNA damage signaling, and checkpoint kinases (Chks) in particular, as a means to sensitize proliferating tumor cells to chemotherapies that damage DNA. 7-Hydroxystaurosporine, or UCN-01, is a clinically relevant and well-studied kinase activity inhibitor that exerts chemosensitizing effects by inhibition of Chk1, and a multitude of Chk1 inhibitors have entered development. Clinical development of UCN-01 has overcome many initial obstacles, but the drug has nevertheless failed to show a high level of clinical activity when combined with chemotherapeutic agents. One very likely reason for the lack of clinical efficacy of Chk1 inhibitors may be that the inhibition of Chk1 causes the compensatory activation of ATM and ERK1/2 pathways. Indeed, inhibition of many enzyme activities, not necessarily components of cell cycle regulation, may block Chk1 inhibitor-induced ERK1/2 activation and enhance the toxicity of Chk1 inhibitors. This review examines the rationally hypothesized actions of Chk1 inhibitors as cell cycle modulatory drugs as well as the impact of Chk1 inhibition upon other cell survival signaling pathways. An understanding of Chk1 inhibition in multiple signaling contexts will be essential to the therapeutic development of Chk1 inhibitors.
authors.affiliation: Department of Neurosurgery, Virginia Commonwealth University, Massey Cancer Center, 401 College Street, Richmond, VA 23298-0035, USA. pdent@vcu.edu
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
authors.forename: Adly
authors.initials: A
authors.lastname: Yacoub
authors.forename: Yun
authors.initials: Y
authors.lastname: Dai
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D004359:Drug Therapy, Combination / Q000379:methods; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism*
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1