Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia.
Entry into the cell cycle is mediated by cyclin-dependent kinase 4/6 (CDK4/6) activation, followed by CDK2 activation. We found that pharmacologic inhibition of the Flt3 internal tandem duplication (ITD), a mutated receptor tyrosine kinase commonly found in patients with acute myelogenous leukemia (AML), led to the down-regulation of cyclin D2 and D3 followed by retinoblastoma protein (pRb) dephosphorylation and G(1) cell-cycle arrest. This implicated the D-cyclin-CDK4/6 complex as a downstream effector of Flt3 ITD signaling. Indeed, single-agent PD0332991, a selective CDK4/6 inhibitor, caused sustained cell-cycle arrest in Flt3 ITD AML cell lines and prolonged survival in an in vivo model of Flt3 ITD AML. PD0332991 caused an initial cell-cycle arrest in well-established Flt3 wild-type (wt) AML cell lines, but this was overcome by down-regulation of p27(Kip) and reactivation of CDK2. This acquired resistance was not observed in a Flt3 ITD and a Flt3 wt sample from a patient with primary AML. In summary, the mechanism of cell-cycle arrest after treatment of Flt3 ITD AML with a Flt3 inhibitor involves down-regulation of cyclin D2 and D3. As such, CDK4/6 can be a therapeutic target in Flt3 ITD AML but also in primary Flt3 wt AML. Finally, acquired resistance to CDK4/6 inhibition can arise through activation CDK2.
Wang
Lisheng
L
Department of Pharmacology, The Ohio State University, Columbus, OH 43210, USA.
Wang
Jie
J
Blaser
Bradley W
BW
Duchemin
Anne-Marie
AM
Kusewitt
Donna F
DF
Liu
Tom
T
Caligiuri
Michael A
MA
Briesewitz
Roger
R
D000208:Acute Disease; D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism; D049109:Cell Proliferation; D056742:Cyclin D2; D056743:Cyclin D3; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D047468:Immunoprecipitation; D007211:Indoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
C513935:5-((5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl)-N-(2-hydroxy-3-morpholin-4-ylpropyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide; C080336:CCND2 protein, human; C534696:CCND3 protein, human; C436291:CDKN1B protein, human; C534697:Ccnd3 protein, mouse; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010879:Piperazines; D011725:Pyridines; D011758:Pyrroles; D016160:Retinoblastoma Protein; C475928:THRX 165724; D050760:Cyclin-Dependent Kinase Inhibitor p27; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib