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

作者：Piovan Erich; Yu Jiyang; Tosello Valeria; Herranz Daniel; Ambesi Impiombato Alberto; Da Silva Ana Carolina; Sanchez Martin Marta; Perez Garcia Arianne; Rigo Isaura; Castillo Mireia; Indraccolo Stefano; Cross Justin R; de Stanchina Elisa; Paietta Elisabeth; Racevskis Janis; Rowe Jacob M; Tallman Martin S; Basso Giuseppe; Meijerink Jules P; Cordon Cardo Carlos; Califano Andrea^*; Ferrando Adolfo A

来源：Cancer Cell, 2013, 24(6): 766-776.

DOI：10.1016/j.ccr.2013.10.022

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 glubocorticoid 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.

• 出版日期2013-12-9