Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels un composé appelé MK2206, un inhibiteur de la signalisation AKT, permet de surmonter une résistance aux glucocorticoïdes dans le traitement d'une leucémie lymphoblastique aiguë de type T
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. "AKT1 directly phosphorylates the NR3C1 glucocorticoid receptor protein "AKT-mediated S134 phosphorylation blocks nuclear translocation of NR3C1 "PTEN loss and AKT1 activation induce glucocorticoid resistance in T-ALL "Pharmacologic inhibition of AKT1 reverses glucocorticoid resistance in T-ALL