Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia

Cancer Cell. 2013 Dec 9;24(6):766-76. doi: 10.1016/j.ccr.2013.10.022. Epub 2013 Nov 27.

Abstract

Glucocorticoid resistance is a major driver of therapeutic failure in T cell acute lymphoblastic leukemia (T-ALL). Here, we identify the AKT1 kinase as a major negative regulator of the NR3C1 glucocorticoid receptor protein activity driving glucocorticoid resistance in T-ALL. Mechanistically, AKT1 impairs glucocorticoid-induced gene expression by direct phosphorylation of NR3C1 at position S134 and blocking glucocorticoid-induced NR3C1 translocation to the nucleus. Moreover, we demonstrate that loss of PTEN and consequent AKT1 activation can effectively block glucocorticoid-induced apoptosis and induce resistance to glucocorticoid therapy. Conversely, pharmacologic inhibition of AKT with MK2206 effectively restores glucocorticoid-induced NR3C1 translocation to the nucleus, increases the response of T-ALL cells to glucocorticoid therapy, and effectively reverses glucocorticoid resistance in vitro and in vivo.

Publication types

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

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Dexamethasone / therapeutic use*
  • Drug Resistance, Neoplasm
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • Humans
  • Mice
  • PTEN Phosphohydrolase / physiology
  • Phosphorylation
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / physiology
  • Receptors, Glucocorticoid / metabolism

Substances

  • Heterocyclic Compounds, 3-Ring
  • MK 2206
  • NR3C1 protein, human
  • Receptors, Glucocorticoid
  • Dexamethasone
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase

Associated data

  • GEO/GSE32215
  • GEO/GSE41062