Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL⁺ leukemia cells.

Abstract

Interactions between the dual BCR/ABL and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in BCR/ABL(+) leukemia cells, particularly imatinib-resistant cells, including those with the T315I mutation. Bosutinib blocked PF-00477736-induced ERK1/2 activation and sharply increased apoptosis in association with Mcl-1 inhibition, p34(cdc2) dephosphorylation, BimEL up-regulation, and DNA damage in imatinib-resistant CML or Ph(+) ALL cell lines. Inhibition of Src or MEK1 by shRNA significantly enhanced PF-0047736 lethality. Bosutinib/PF-00477736 co-treatment also potentiated cell death in CD34(+) CML patient samples, including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations, but was minimally toxic to normal CD34(+) cells. Finally, combined in vivo treatment significantly suppressed BaF3/T315I tumor growth and prolonged survival in an allogeneic mouse model. Together, these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph(+) ALL.

• Authors: Tri Nguyen, Elisa Hawkins, Akhil Kolluri, Maciej Kmieciak, Haeseong Park, Hui Lin, Steven Grant
• Journal: Leukemia research (Leuk Res) Vol. 39 Issue 1 Pg. 65-71 (Jan 2015) ISSN: 1873-5835 [Electronic] England
• PMID: 25465126 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Aniline Compounds
• Antineoplastic Agents
• Benzamides
• Benzodiazepinones
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Nitriles
• PF 00477736
• Piperazines
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• Quinolines
• bosutinib
• Imatinib Mesylate
• Protein Kinases
• Fusion Proteins, bcr-abl
• CHEK1 protein, human
• Checkpoint Kinase 1
• Chek1 protein, mouse
• MAPK1 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• MAP Kinase Kinase 1
• MAP2K1 protein, human

Topics

• Amino Acid Substitution
• Aniline Compounds (agonists, pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Benzamides
• Benzodiazepinones (agonists, pharmacology)
• Checkpoint Kinase 1
• Drug Resistance, Neoplasm (drug effects, genetics)
• Drug Synergism
• Fusion Proteins, bcr-abl (antagonists & inhibitors, genetics, metabolism)
• Humans
• Imatinib Mesylate
• K562 Cells
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, genetics, metabolism, pathology)
• MAP Kinase Kinase 1 (genetics, metabolism)
• MAP Kinase Signaling System (drug effects, genetics)
• Mice
• Mice, Nude
• Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 3 (genetics, metabolism)
• Mutation, Missense
• Myeloid Cell Leukemia Sequence 1 Protein
• Nitriles (agonists, pharmacology)
• Piperazines
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, metabolism, pathology)
• Protein Kinase Inhibitors
• Protein Kinases (metabolism)
• Pyrazoles (agonists, pharmacology)
• Pyrimidines
• Quinolines (agonists, pharmacology)
• Xenograft Model Antitumor Assays