Abstract
Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G(1) arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G(1) and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G(1) block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects*
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Apoptosis / genetics
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Boronic Acids / administration & dosage
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Boronic Acids / pharmacology
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Bortezomib
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Cell Cycle / drug effects
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Cell Cycle / genetics
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Cell Line, Tumor
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Cyclin-Dependent Kinase 4 / antagonists & inhibitors
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Cyclin-Dependent Kinase 6 / antagonists & inhibitors
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Cytotoxins / administration & dosage
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Cytotoxins / pharmacology
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Down-Regulation / drug effects
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Down-Regulation / genetics
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Drug Resistance, Neoplasm / drug effects
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Drug Synergism
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G1 Phase Cell Cycle Checkpoints / drug effects*
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G1 Phase Cell Cycle Checkpoints / genetics
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G1 Phase Cell Cycle Checkpoints / physiology
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Interferon Regulatory Factors / genetics*
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Interferon Regulatory Factors / metabolism
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Mice, Transgenic
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / genetics
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Multiple Myeloma / pathology
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / pharmacology*
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Pyrazines / administration & dosage
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Pyrazines / pharmacology
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Substrate Specificity
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Time Factors
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Xenograft Model Antitumor Assays
Substances
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Boronic Acids
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Cytotoxins
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Interferon Regulatory Factors
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Protein Kinase Inhibitors
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Pyrazines
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interferon regulatory factor-4
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Bortezomib
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6