AKT Drives Glucocorticoid Resistance in T-ALL

Glucocorticoids such as dexamethasone are essential components of therapy for T-cell acute lymphoblastic leukemia (T-ALL) and other lymphoid malignancies. Primary glucocorticoid resistance, characterized by ineffective cytoreduction after 1 week of glucocorticoid therapy, occurs frequently in T-ALL and is associated with poor outcome. Glucocorticoids act by binding to nuclear receptor subfamily 3, group C, member 1 (NR3C1, otherwise known as the glucocorticoid receptor) in the cytoplasm, which then shuttles to the nucleus upon ligand binding to regulate glucocorticoid-dependent gene expression that induces apoptosis in T-ALL cells. Given that PI3K–AKT signaling promotes T-cell transformation and that increased AKT1 activity has been associated with glucocorticoid resistance in patients with ALL, Piovan and colleagues hypothesized that AKT1 might interfere with NR3C1 function. AKT1 bound NR3C1 in T-ALL lymphoblasts and phosphorylated NR3C1 on serine 134, suggesting that AKT1 might directly affect NR3C1 activity. Indeed, phosphorylation of NR3C1 by AKT 1 blocked NR3C1 translocation to the nucleus in response to glucocorticoid treatment and suppressed activation of glucocorticoid-responsive genes. Based on these findings, the authors tested whether pharmacologic inhibition of AKT1 could restore glucocorticoid sensitivity in resistant T-ALL and found that combining an AKT inhibitor with dexamethasone restored apoptosis in glucocorticoid-resistant T-ALL cell lines in association with increased NR3C1 nuclear translocation. Moreover, AKT1 inhibition significantly increased the antileukemic activity of dexamethasone in primary human glucocorticoid-resistant T-ALL xenografts, and the combination of an AKT inhibitor and dexamethasone significantly decreased tumor burden and increased survival in a genetically engineered mouse model of glucocorticoid-resistant T-ALL. Although these findings do not preclude roles for additional mechanisms downstream of AKT1 in glucocorticoid resistance, they show that AKT1 can directly inactivate NR3C1 and provide support for targeting AKT1 to reverse glucocorticoid resistance in T-ALL.

Piovan E, Yu J, Tosello V, Herranz D, Ambesi-Impiombato A, Da Silva AC, et al. Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia. Cancer Cell 2013;24:766–76.