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

Erich Piovan, Jiyang Yu, Valeria Tosello, Daniel Herranz, Alberto Ambesi-Impiombato, Ana Carolina DaSilva, Marta Sanchez-Martin, Arianne Perez-Garcia, Isaura Rigo, Mireia Castillo, Stefano Indraccolo, Justin R. Cross, Elisa deStanchina, Elisabeth Paietta, Janis Racevskis, Jacob M. Rowe, Martin S. Tallman, Giuseppe Basso, Jules P. Meijerink, Carlos Cordon-CardoAndrea Califano, Adolfo A. Ferrando

Research output: Contribution to journalArticlepeer-review

146 Scopus citations

Abstract

Glucocorticoid resistance is a major driver of therapeutic failure in Tcell 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 invitro and invivo.

Original languageEnglish (US)
Pages (from-to)766-776
Number of pages11
JournalCancer Cell
Volume24
Issue number6
DOIs
StatePublished - Dec 9 2013

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia'. Together they form a unique fingerprint.

Cite this