NDLI: Modulation of Glucocorticoid Resistance in Pediatric T-cell Acute Lymphoblastic Leukemia by Increasing BIM Expression with the PI3K/mTOR Inhibitor BEZ235.

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Modulation of Glucocorticoid Resistance in Pediatric T-cell Acute Lymphoblastic Leukemia by Increasing BIM Expression with the PI3K/mTOR Inhibitor BEZ235.

Content Provider	Semantic Scholar
Author	Hall, Connor P. Reynolds, C. Patrick Kang, Min Hyung
Copyright Year	2016
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.
Starting Page	347
Ending Page	348
Page Count	2
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://clincancerres.aacrjournals.org/content/clincanres/22/3/621.full.pdf
Alternate Webpage(s)	http://clincancerres.aacrjournals.org/content/clincanres/early/2015/06/16/1078-0432.CCR-15-0114.full.pdf
PubMed reference number	26080839v1
Alternate Webpage(s)	https://doi.org/10.1158/1078-0432.CCR-15-0114
DOI	10.1158/1078-0432.ccr-15-0114
Journal	Clinical cancer research : an official journal of the American Association for Cancer Research
Volume Number	22
Issue Number	3
Language	English
Access Restriction	Open
Subject Keyword	Acute lymphocytic leukemia Apoptosis BCL2L11 wt Allele BEZ235 Cultured Cell Line Dexamethasone Dual FRAP1 protein, human Glucocorticoid Receptor Deficiency Immunoblotting Leukemia, B-Cell Multi-Drug Resistance Null Value Patients Precursor Cell Lymphoblastic Leukemia Lymphoma Proto-Oncogene Proteins c-akt Reverse Transcriptase Polymerase Chain Reaction Xenograft type of graft cellular targeting lymphoblast mTOR Inhibitor
Content Type	Text
Resource Type	Article

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Modulation of Glucocorticoid Resistance in Pediatric T-cell Acute Lymphoblastic Leukemia by Increasing BIM Expression with the PI3K/mTOR Inhibitor BEZ235.

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Modulation of Glucocorticoid Resistance in Pediatric T-cell Acute Lymphoblastic Leukemia by Increasing BIM Expression with the PI3K/mTOR Inhibitor BEZ235.

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