Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia.

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.

• Authors: Erich Piovan, Jiyang Yu, Valeria Tosello, Daniel Herranz, Alberto Ambesi-Impiombato, Ana Carolina Da Silva, Marta Sanchez-Martin, Arianne Perez-Garcia, Isaura Rigo, Mireia Castillo, Stefano Indraccolo, Justin R Cross, Elisa de Stanchina, Elisabeth Paietta, Janis Racevskis, Jacob M Rowe, Martin S Tallman, Giuseppe Basso, Jules P Meijerink, Carlos Cordon-Cardo, Andrea Califano, Adolfo A Ferrando
• Journal: Cancer cell (Cancer Cell) Vol. 24 Issue 6 Pg. 766-76 (Dec 09 2013) ISSN: 1878-3686 [Electronic] United States
• PMID: 24291004 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

• 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, physiology)
• Receptors, Glucocorticoid (metabolism)