Abstract
Biochemical and genetic characterization of D-type cyclins, their cyclin D-dependent kinases (CDK4 and CDK6), and the polypeptide CDK4/6 inhibitor p16(INK4)over two decades ago revealed how mammalian cells regulate entry into the DNA synthetic (S) phase of the cell-division cycle in a retinoblastoma protein-dependent manner. These investigations provided proof-of-principle that CDK4/6 inhibitors, particularly when combined with coinhibition of allied mitogen-dependent signal transduction pathways, might prove valuable in cancer therapy. FDA approval of the CDK4/6 inhibitor palbociclib used with the aromatase inhibitor letrozole for breast cancer treatment highlights long-sought success. The newest findings herald clinical trials targeting other cancers.
Significance:
Rapidly emerging data with selective inhibitors of CDK4/6 have validated these cell-cycle kinases as anticancer drug targets, corroborating longstanding preclinical predictions. This review addresses the discovery of these CDKs and their regulators, as well as translation of CDK4/6 biology to positive clinical outcomes and development of rational combinatorial therapies.
©2015 American Association for Cancer Research.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Cell Cycle / drug effects
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Cell Cycle / genetics
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Clinical Trials as Topic
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Cyclin D / genetics
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Cyclin D / metabolism
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Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
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Cyclin-Dependent Kinase 4 / genetics
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Cyclin-Dependent Kinase 4 / metabolism
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Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
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Cyclin-Dependent Kinase 6 / genetics
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Cyclin-Dependent Kinase 6 / metabolism
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism
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Drug Discovery
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Molecular Targeted Therapy*
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Neoplasms / diagnosis
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Neoplasms / drug therapy*
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Neoplasms / genetics
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Neoplasms / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use*
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Signal Transduction / drug effects
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Treatment Outcome
Substances
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Cyclin D
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Cyclin-Dependent Kinase Inhibitor p16
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Protein Kinase Inhibitors
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Phosphatidylinositol 3-Kinases
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6