Journal Article

Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2

Chung, Mingyu, Meyer, Tobias, Daigh, Leighton H., Pack, Lindsey R.

2021

Overview

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. Clinical CDK4/6 inhibitors are used and tested to treat a variety of cancer types. Here, the authors identify that these drugs work in two ways, a known catalytic role to inhibit kinase activity and a newly discovered noncatalytic role to displace CDK inhibitor p21 from CDK4 but not CDK6 complexes.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/19 / 631/80/641 / 631/80/86 / Animals / Cancer / Cell Cycle - drug effects / Cell Line / Cell Nucleus - drug effects / Cell Nucleus - metabolism / Clinical trials / Cyclin D / Cyclin D - metabolism / Cyclin-dependent kinase / Cyclin-dependent kinase 2 / Cyclin-Dependent Kinase 2 - antagonists & inhibitors / Cyclin-Dependent Kinase 2 - genetics / Cyclin-Dependent Kinase 2 - metabolism / Cyclin-dependent kinase 4 / Cyclin-Dependent Kinase 4 - antagonists & inhibitors / Cyclin-Dependent Kinase 4 - genetics / Cyclin-Dependent Kinase 4 - metabolism / Cyclin-Dependent Kinase 6 - antagonists & inhibitors / Cyclin-Dependent Kinase 6 - genetics / Cyclin-Dependent Kinase 6 - metabolism / Cyclin-dependent kinase inhibitor p21 / Cyclin-Dependent Kinase Inhibitor p21 - metabolism / Cyclin-Dependent Kinase Inhibitor p27 - metabolism / Cyclin-dependent kinases / Displacement / Drug development / Epithelial Cells - drug effects / Epithelial Cells - metabolism / Humanities and Social Sciences / Humans / Inhibitors / Kinases / MCF-7 Cells / Mice / Microscopy, Fluorescence / multidisciplinary / Piperazines - pharmacology / Protein Binding / Protein Kinase Inhibitors - pharmacology / Pyridines - pharmacology / Retinal Pigment Epithelium - cytology / Retinal Pigment Epithelium - drug effects / Retinal Pigment Epithelium - metabolism / Science / Science (multidisciplinary) / Stability