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.
Keywords:
BCR/ABL; Bosutinib; Chk1 inhibitor; Chronic myeloid leukemia.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Substitution
-
Aniline Compounds* / agonists
-
Aniline Compounds* / pharmacology
-
Animals
-
Antineoplastic Agents / pharmacology*
-
Benzamides*
-
Benzodiazepinones* / agonists
-
Benzodiazepinones* / pharmacology
-
Checkpoint Kinase 1
-
Drug Resistance, Neoplasm / drug effects*
-
Drug Resistance, Neoplasm / genetics
-
Drug Synergism
-
Fusion Proteins, bcr-abl / antagonists & inhibitors
-
Fusion Proteins, bcr-abl / genetics
-
Fusion Proteins, bcr-abl / metabolism*
-
Humans
-
Imatinib Mesylate
-
K562 Cells
-
Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
-
Leukemia, Lymphocytic, Chronic, B-Cell / genetics
-
Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
-
Leukemia, Lymphocytic, Chronic, B-Cell / pathology
-
MAP Kinase Kinase 1 / genetics
-
MAP Kinase Kinase 1 / metabolism
-
MAP Kinase Signaling System / drug effects
-
MAP Kinase Signaling System / genetics
-
Mice
-
Mice, Nude
-
Mitogen-Activated Protein Kinase 1 / genetics
-
Mitogen-Activated Protein Kinase 1 / metabolism
-
Mitogen-Activated Protein Kinase 3 / genetics
-
Mitogen-Activated Protein Kinase 3 / metabolism
-
Mutation, Missense
-
Myeloid Cell Leukemia Sequence 1 Protein
-
Nitriles* / agonists
-
Nitriles* / pharmacology
-
Piperazines*
-
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
-
Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
-
Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
-
Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
-
Protein Kinase Inhibitors*
-
Protein Kinases / metabolism*
-
Pyrazoles* / agonists
-
Pyrazoles* / pharmacology
-
Pyrimidines*
-
Quinolines* / agonists
-
Quinolines* / pharmacology
-
Xenograft Model Antitumor Assays
Substances
-
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