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

Clin Cancer Res. 2016 Feb 1;22(3):621-32. doi: 10.1158/1078-0432.CCR-15-0114. Epub 2015 Jun 16.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / metabolism
  • Bcl-2-Like Protein 11
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dexamethasone / pharmacology
  • Disease Models, Animal
  • Drug Resistance, Neoplasm*
  • Drug Synergism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Glucocorticoids / pharmacology
  • Humans
  • Imidazoles / pharmacology*
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / mortality
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Quinolines / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Glucocorticoids
  • Imidazoles
  • Membrane Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Quinolines
  • Dexamethasone
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • dactolisib