Prolonged early G(1) arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4.
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.
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Xiangao
X
Huang
Maurizio
M
Di Liberto
David
D
Jayabalan
Jun
J
Liang
Scott
S
Ely
Jamieson
J
Bretz
Arthur L
AL
Shaffer
Tracey
T
Louie
Isan
I
Chen
Sophia
S
Randolph
William C
WC
Hahn
Louis M
LM
Staudt
Ruben
R
Niesvizky
Malcolm A S
MA
Moore
Selina
S
Chen-Kiang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D003603:Cytotoxins / Q000008:administration & dosage / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology; D013379:Substrate Specificity; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays; D000099218:Interferon Regulatory Factor-4
D001897:Boronic Acids; D000069286:Bortezomib; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D003603:Cytotoxins; D050835:Interferon Regulatory Factors; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D000099218:Interferon Regulatory Factor-4