2015/12/12 by Charles J. Sherr, David Beach, Geoffrey I. Shapiro · 1 citation
Medicine · #Advanced Breast Cancer Therapies #Cancer-related Molecular Pathways #Cancer Mechanisms and Therapy
paper · doi:10.1158/2159-8290.cd-15-0894
openalex publication_date 2015/12/12 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
UNLABELLED: 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.