Abstract
Purpose:
The aim of our study is to evaluate the preclinical therapeutic activity and mechanism of action of BEZ235, a dual PI3K/mTOR inhibitor, in combination with dexamethasone in acute lymphoblastic leukemia (ALL).
Experimental design:
The cytotoxic effects of BEZ235 and dexamethasone as single agents and in combination were assessed in a panel of ALL cell lines and xenograft models. The underlying mechanism of BEZ235 and dexamethasone was evaluated using immunoblotting, TaqMan RT-PCR, siRNA, immunohistochemistry, and immunoprecipitation.
Results:
Inhibition of the PI3K/AKT/mTOR pathway with the dual PI3K/mTOR inhibitor BEZ235 enhanced dexamethasone-induced anti-leukemic activity in in vitro (continuous cell lines and primary ALL cultures) and systemic in vivo models of T-ALL (including a patient-derived xenograft). Through inhibition of AKT1, BEZ235 was able to alleviate AKT1-mediated suppression of dexamethasone-induced apoptotic pathways leading to increased expression of the proapoptotic BCL-2 protein BIM. Downregulation of MCL-1 by BEZ235 further contributed to the modulation of dexamethasone resistance by increasing the amount of BIM available to induce apoptosis, especially in PTEN-null T-ALL where inhibition of AKT only partially overcame AKT-induced BIM suppression.
Conclusions:
Our data support the further investigation of agents targeting the PI3K/mTOR pathway to modulate glucocorticoid resistance in T-ALL.
©2015 American Association for Cancer Research.
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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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Apoptosis Regulatory Proteins / genetics*
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Apoptosis Regulatory Proteins / metabolism
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Bcl-2-Like Protein 11
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Cell Line, Tumor
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Cell Survival / drug effects
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Dexamethasone / pharmacology
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Disease Models, Animal
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Drug Resistance, Neoplasm*
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Drug Synergism
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Female
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Gene Expression Regulation, Neoplastic / drug effects*
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Glucocorticoids / pharmacology
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Humans
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Imidazoles / pharmacology*
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism
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Myeloid Cell Leukemia Sequence 1 Protein / genetics
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / mortality
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Quinolines / pharmacology*
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Glucocorticoids
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Imidazoles
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Membrane Proteins
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Myeloid Cell Leukemia Sequence 1 Protein
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Quinolines
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Dexamethasone
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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dactolisib