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Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2.
- Source :
-
Nature communications [Nat Commun] 2021 Jun 07; Vol. 12 (1), pp. 3356. Date of Electronic Publication: 2021 Jun 07. - Publication Year :
- 2021
-
Abstract
- Since their discovery as drivers of proliferation, cyclin-dependent kinases (CDKs) have been considered therapeutic targets. Small molecule inhibitors of CDK4/6 are used and tested in clinical trials to treat multiple cancer types. Despite their clinical importance, little is known about how CDK4/6 inhibitors affect the stability of CDK4/6 complexes, which bind cyclins and inhibitory proteins such as p21. We develop an assay to monitor CDK complex stability inside the nucleus. Unexpectedly, treatment with CDK4/6 inhibitors-palbociclib, ribociclib, or abemaciclib-immediately dissociates p21 selectively from CDK4 but not CDK6 complexes. This effect mediates indirect inhibition of CDK2 activity by p21 but not p27 redistribution. Our work shows that CDK4/6 inhibitors have two roles: non-catalytic inhibition of CDK2 via p21 displacement from CDK4 complexes, and catalytic inhibition of CDK4/6 independent of p21. By broadening the non-catalytic displacement to p27 and CDK6 containing complexes, next-generation CDK4/6 inhibitors may have improved efficacy and overcome resistance mechanisms.
- Subjects :
- Animals
Cell Cycle drug effects
Cell Line
Cell Nucleus drug effects
Cell Nucleus metabolism
Cyclin-Dependent Kinase 2 genetics
Cyclin-Dependent Kinase 2 metabolism
Cyclin-Dependent Kinase 4 genetics
Cyclin-Dependent Kinase 4 metabolism
Cyclin-Dependent Kinase 6 genetics
Cyclin-Dependent Kinase 6 metabolism
Cyclin-Dependent Kinase Inhibitor p27 metabolism
Epithelial Cells drug effects
Epithelial Cells metabolism
Humans
MCF-7 Cells
Mice
Microscopy, Fluorescence
Piperazines pharmacology
Protein Binding
Pyridines pharmacology
Retinal Pigment Epithelium cytology
Retinal Pigment Epithelium drug effects
Retinal Pigment Epithelium metabolism
Cyclin D metabolism
Cyclin-Dependent Kinase 2 antagonists & inhibitors
Cyclin-Dependent Kinase 4 antagonists & inhibitors
Cyclin-Dependent Kinase 6 antagonists & inhibitors
Cyclin-Dependent Kinase Inhibitor p21 metabolism
Protein Kinase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 12
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 34099663
- Full Text :
- https://doi.org/10.1038/s41467-021-23612-z