Journal
CANCER DISCOVERY
Volume 6, Issue 4, Pages 353-367Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-15-0894
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Funding
- Howard Hughes Medical Institute
- NIH Cancer Center [CA-21765]
- ALSAC of St. Jude Children's Research Hospital
- NIH [R01-CA090687, P50-CA168504]
- Susan G. Komen investigator-initiated research grant [IIR12223953]
- Pfizer
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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. (C) 2015 AACR.
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