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 journalArticle

118 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

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ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Piovan, E., Yu, J., Tosello, V., Herranz, D., Ambesi-Impiombato, A., DaSilva, A. C., Sanchez-Martin, M., Perez-Garcia, A., Rigo, I., Castillo, M., Indraccolo, S., Cross, J. R., deStanchina, E., Paietta, E., Racevskis, J., Rowe, J. M., Tallman, M. S., Basso, G., Meijerink, J. P., ... Ferrando, A. A. (2013). Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia. Cancer Cell, 24(6), 766-776. https://doi.org/10.1016/j.ccr.2013.10.022