Abstract
Mediators of PI3K/AKT signaling have been implicated in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). Studies have shown that inhibitors of PI3K/AKT signaling, such as wortmannin and LY294002, are able to inhibit CML and AML cell proliferation and synergize with targeted tyrosine kinase inhibitors. We investigated the ability of BAG956, a dual PI3K/PDK-1 inhibitor, to be used in combination with inhibitors of BCR-ABL and mutant FLT3, as well as with the mTOR inhibitor, rapamycin, and the rapamycin derivative, RAD001. BAG956 was shown to block AKT phosphorylation induced by BCR-ABL-, and induce apoptosis of BCR-ABL-expressing cell lines and patient bone marrow cells at concentrations that also inhibit PI3K signaling. Enhancement of the inhibitory effects of the tyrosine kinase inhibitors, imatinib and nilotinib, by BAG956 was demonstrated against BCR-ABL expressing cells both in vitro and in vivo. We have also shown that BAG956 is effective against mutant FLT3-expressing cell lines and AML patient bone marrow cells. Enhancement of the inhibitory effects of the tyrosine kinase inhibitor, PKC412, by BAG956 was demonstrated against mutant FLT3-expressing cells. Finally, BAG956 and rapamycin/RAD001 were shown to combine in a nonantagonistic fashion against BCR-ABL- and mutant FLT3-expressing cells both in vitro and in vivo.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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3-Phosphoinositide-Dependent Protein Kinases
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Synergism
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Enzyme Activation / drug effects
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Enzyme Activation / genetics
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Enzyme Inhibitors / agonists
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use
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Fusion Proteins, bcr-abl
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Enzymologic / genetics
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Gene Expression Regulation, Leukemic / drug effects
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Gene Expression Regulation, Leukemic / genetics
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Humans
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Imidazoles / pharmacology*
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Imidazoles / therapeutic use
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Leukemia, Myeloid, Acute / drug therapy*
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Leukemia, Myeloid, Acute / enzymology
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Leukemia, Myeloid, Acute / genetics
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Male
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Mice
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Mice, Nude
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Mutation*
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Phosphatidylinositol 3-Kinases / biosynthesis
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Phosphatidylinositol 3-Kinases / genetics
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Phosphoinositide-3 Kinase Inhibitors*
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Phosphorylation / drug effects
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Protein Kinases / genetics
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / genetics
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / biosynthesis
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Protein-Tyrosine Kinases / genetics
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Quinolines / pharmacology*
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Quinolines / therapeutic use
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Signal Transduction / drug effects
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Signal Transduction / genetics
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TOR Serine-Threonine Kinases
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fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
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fms-Like Tyrosine Kinase 3 / biosynthesis*
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fms-Like Tyrosine Kinase 3 / genetics
Substances
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BAG956
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Enzyme Inhibitors
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Imidazoles
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Phosphoinositide-3 Kinase Inhibitors
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Quinolines
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Protein Kinases
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MTOR protein, human
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mTOR protein, mouse
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FLT3 protein, human
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Flt3 protein, mouse
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Protein-Tyrosine Kinases
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fms-Like Tyrosine Kinase 3
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Fusion Proteins, bcr-abl
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3-Phosphoinositide-Dependent Protein Kinases
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases