Abstract
CDK4/6 inhibitors are among a new generation of therapeutics. Building upon the striking success of the combination of CDK4/6 inhibitors and the hormone receptor antagonist letrozole in breast cancer, many other combinations have recently entered clinical trials in multiple diseases. To achieve maximal benefit with CDK4/6 inhibitors it will be critical to understand the cellular mechanisms by which they act. Here we highlight the mechanisms by which CDK4/6 inhibitors can exert their anti-tumor activities beyond simply enforcing cytostatic growth arrest, and discuss how this knowledge may inform new combinations, improve outcomes, and modify dosing schedules in the future.
Keywords:
CDK4/6 inhibitors; abemaciclib; metabolism; palbociclib; ribociclib; senescence; tumor microenvironment.
Copyright © 2018 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Animals
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / therapeutic use*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Cell Cycle Checkpoints / drug effects*
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Cell Proliferation / drug effects
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Cellular Senescence / drug effects
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Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
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Cyclin-Dependent Kinase 4 / metabolism
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Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
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Cyclin-Dependent Kinase 6 / metabolism
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Drug Design*
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Humans
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Molecular Targeted Therapy
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Neoplasms / drug therapy*
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Neoplasms / enzymology
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Neoplasms / pathology
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Protein Kinase Inhibitors / adverse effects
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Protein Kinase Inhibitors / therapeutic use*
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Signal Transduction
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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CDK4 protein, human
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CDK6 protein, human
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6