Targeting checkpoint kinase 1 in cancer therapeutics.
Progression through the cell cycle is monitored by surveillance mechanisms known as cell cycle checkpoints. Our knowledge of the biochemical nature of checkpoint regulation during an unperturbed cell cycle and following DNA damage has expanded tremendously over the past decade. We now know that dysfunction in cell cycle checkpoints leads to genomic instability and contributes to tumor progression, and most agents used for cancer therapy, such as cytotoxic chemotherapy and ionizing radiation, also activate cell cycle checkpoints. Understanding how checkpoints are regulated is therefore important from the points of view of both tumorigenesis and cancer treatment. In this review, we present an overview of the molecular hierarchy of the checkpoint signaling network and the emerging role of checkpoint targets, especially checkpoint kinase 1, in cancer therapy. Further, we discuss the results of recent clinical trials involving the nonspecific checkpoint kinase 1 inhibitor, UCN-01, and the challenges we face with this new therapeutic approach.
Tse
Archie N
AN
Authors' Affiliations: Gastrointestinal Oncology Service and Melanoma and Sarcoma Service, Division of Solid Tumor Oncology and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York.
Carvajal
Richard
R
Schwartz
Gary K
GK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D000071877:Checkpoint Kinase 1; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1