Targeting CDK4 and CDK6: From Discovery to Therapy
Charles J Sherr1, David Beach2, Geoffrey I Shapiro3
1Howard 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.
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.
Insights
Selective inhibitors targeting cyclin-dependent kinases 4 and 6 (CDK4/6) are now FDA-approved cancer therapies. This validates CDK4/6 as crucial drug targets, paving the way for new combination treatments against various cancers.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Decades of research elucidated the role of D-type cyclins, cyclin-dependent kinases (CDK4 and CDK6), and p16(INK4) in regulating cell cycle progression.
- The retinoblastoma protein (Rb) pathway is central to mammalian cell entry into the DNA synthetic (S) phase.
Purpose of the Study:
- To review the discovery and characterization of CDK4/6 and their regulators.
- To discuss the translation of CDK4/6 biology into clinical applications for cancer therapy.
- To highlight the development of rational combinatorial therapies targeting CDK4/6.
Main Methods:
- Biochemical and genetic characterization of cell cycle regulators.
- Preclinical investigations into the therapeutic potential of CDK4/6 inhibitors.
- Analysis of clinical trial data for CDK4/6-targeted therapies.
Main Results:
- CDK4/6 inhibitors, especially in combination therapies, show significant promise in cancer treatment.
- FDA approval of palbociclib with letrozole for breast cancer demonstrates clinical success.
- Emerging data support CDK4/6 inhibitors as effective anticancer drug targets.
Conclusions:
- Selective CDK4/6 inhibitors have validated these kinases as viable anticancer drug targets.
- The findings support the development of novel combinatorial strategies for cancer treatment.
- Ongoing clinical trials are exploring CDK4/6 inhibitors in a broader range of cancers.
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