title: Targeting CDK4 and CDK6: From Discovery to Therapy.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD. Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee. geoffrey_shapiro@dfci.harvard.edu sherr@stjude.org.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Sherr
authors.affiliation: The Blizard Institute, Barts and the London School of Medicine and Dentistry, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Beach
authors.affiliation: Early Drug Development Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. geoffrey_shapiro@dfci.harvard.edu sherr@stjude.org.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002986:Clinical Trials as Topic; D056741:Cyclin D / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D055808:Drug Discovery; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D056741:Cyclin D; D019941:Cyclin-Dependent Kinase Inhibitor p16; D047428:Protein Kinase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6