A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6.
Cell cycle deregulation is central to the initiation and fatality of multiple myeloma, the second most common hematopoietic cancer, although impaired apoptosis plays a critical role in the accumulation of myeloma cells in the bone marrow. The mechanism for intermittent, unrestrained proliferation of myeloma cells is unknown, but mutually exclusive activation of cyclin-dependent kinase 4 (Cdk4)-cyclin D1 or Cdk6-cyclin D2 precedes proliferation of bone marrow myeloma cells in vivo. Here, we show that by specific inhibition of Cdk4/6, the orally active small-molecule PD 0332991 potently induces G(1) arrest in primary bone marrow myeloma cells ex vivo and prevents tumor growth in disseminated human myeloma xenografts. PD 0332991 inhibits Cdk4/6 proportional to the cycling status of the cells independent of cellular transformation and acts in concert with the physiologic Cdk4/6 inhibitor p18(INK4c). Inhibition of Cdk4/6 by PD 0332991 is not accompanied by induction of apoptosis. However, when used in combination with a second agent, such as dexamethasone, PD 0332991 markedly enhances the killing of myeloma cells by dexamethasone. PD 0332991, therefore, represents the first promising and specific inhibitor for therapeutic targeting of Cdk4/6 in multiple myeloma and possibly other B-cell cancers.
Baughn
Linda B
LB
Department of Pathology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Di Liberto
Maurizio
M
Wu
Kaida
K
Toogood
Peter L
PL
Louie
Tracey
T
Gottschalk
Rachel
R
Niesvizky
Ruben
R
Cho
Hearn
H
Ely
Scott
S
Moore
Malcolm A S
MA
Chen-Kiang
Selina
S
D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D050763:Cyclin-Dependent Kinase Inhibitor p18; D010879:Piperazines; D011725:Pyridines; D003907:Dexamethasone; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib