Cancer discovery, 2016-04, Vol.6 (4), p.353-367
2016
Details
- Autor(en) / Beteiligte
- Titel
- Targeting CDK4 and CDK6: From Discovery to Therapy
- Ist Teil von
- Cancer discovery, 2016-04, Vol.6 (4), p.353-367
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2016
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2159-8274eISSN: 2159-8290DOI: 10.1158/2159-8290.cd-15-0894Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4821753
- Format
- –
- Schlagworte
- Animals, Antineoplastic Combined Chemotherapy Protocols - therapeutic use, Cell Cycle - drug effects, Cell Cycle - genetics, Clinical Trials as Topic, Cyclin D - genetics, Cyclin D - metabolism, Cyclin-Dependent Kinase 4 - antagonists & inhibitors, Cyclin-Dependent Kinase 4 - genetics, Cyclin-Dependent Kinase 4 - metabolism, Cyclin-Dependent Kinase 6 - antagonists & inhibitors, Cyclin-Dependent Kinase 6 - genetics, Cyclin-Dependent Kinase 6 - metabolism, Cyclin-Dependent Kinase Inhibitor p16 - genetics, Cyclin-Dependent Kinase Inhibitor p16 - metabolism, Drug Discovery, Gene Expression Regulation, Neoplastic - drug effects, Humans, Molecular Targeted Therapy, Neoplasms - diagnosis, Neoplasms - drug therapy, Neoplasms - genetics, Neoplasms - metabolism, Phosphatidylinositol 3-Kinases - metabolism, Phosphorylation, Protein Kinase Inhibitors - pharmacology, Protein Kinase Inhibitors - therapeutic use, Signal Transduction - drug effects, Treatment Outcome