期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-23612-z
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资金
- National Institute of General Medical Sciences of the National Institutes of Health [F32GM125246]
- Stanford Medical Scientist Training Program NIH [T32GM007365]
- National Institute of Aging of the National Institutes of Health [F30AG060634]
- National Institute of General Medical Sciences [GM127026]
CDK4/6 inhibitors not only suppress CDK2 activity by displacing p21 from CDK4 complexes, but also catalytically inhibit CDK4/6 independently of p21, potentially by broadening the displacement to p27 and CDK6-containing complexes, with the aim of increasing efficacy and overcoming resistance mechanisms.
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.
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