Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia
| Autor: | Michael A. Caligiuri, Anne Marie Duchemin, Donna Frances Kusewitt, Jie Wang, Bradley W. Blaser, Roger Briesewitz, Tom Liu, Lisheng Wang |
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| Rok vydání: | 2007 |
| Předmět: |
Indoles
Pyridines Mice SCID Retinoblastoma Protein Biochemistry Piperazines Mice fluids and secretions hemic and lymphatic diseases Tumor Cells Cultured Cyclin D2 Cyclin D3 Phosphorylation biology Intracellular Signaling Peptides and Proteins Retinoblastoma protein Myeloid leukemia hemic and immune systems Hematology Leukemia Leukemia Myeloid Acute Disease embryonic structures Cyclin-Dependent Kinase Inhibitor p27 Signal Transduction FLT3 Internal Tandem Duplication Morpholines Blotting Western Immunology Bone Marrow Cells Cyclins medicine Animals Humans Immunoprecipitation Pyrroles neoplasms Cell Proliferation Cyclin-dependent kinase 4 Cyclin-dependent kinase 2 G1 Phase Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase 6 Cell Biology medicine.disease fms-Like Tyrosine Kinase 3 Mutation biology.protein Cancer research |
| Zdroj: | Blood. 110:2075-2083 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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 G1 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 p27Kip 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. |
| Databáze: | OpenAIRE |
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