Reversal of glucocorticoid resistance by AKT inhibition in T-ALL. Homo sapiens

Glucocorticoid resistance is a major driver of therapeutic failure in T-cell acute lymphoblastic leukemia (T-ALL). Here we used a systems biology approach, based on the reverse engineering of signaling regulatory networks, which identified the AKT1 kinase as a signaling factor driving glucocorticoid resistance in T-ALL. Indeed, activation of AKT1 in T-ALL lymphoblasts impairs glucocorticoid-induced apoptosis. Mechanistically, AKT1 directly phosphorylates the glucocorticoid receptor NR3C1 protein at position S134 and blocks glucocorticoid-induced NR3C1 translocation to the nucleus. Consistently, inhibition of AKT1 with MK-2206 increases the response of T-ALL cells to glucocorticoid therapy both in T-ALL cell lines and in primary patient samples thus effectively reversing glucocorticoid resistance in vitro and in vivo. These results warrant the clinical testing of ATK1 inhibitors and glucocorticoids, in combination, for the treatment of T-ALL. Overall design: This study includes 228 T-ALL samples of which 117 samples are re-analysis of GSE26713.

糖皮质激素抵抗（glucocorticoid resistance）是T细胞急性淋巴细胞白血病（T-cell acute lymphoblastic leukemia，简称T-ALL）治疗失败的主要驱动因素。本研究基于信号调控网络逆向工程的系统生物学分析策略，鉴定出AKT1激酶（AKT1 kinase）是驱动T-ALL发生糖皮质激素抵抗的信号因子。实验证实，在T-ALL淋巴母细胞中激活AKT1，会抑制糖皮质激素诱导的细胞凋亡。从分子机制层面来看，AKT1可直接对糖皮质激素受体NR3C1蛋白的S134位点进行磷酸化修饰，并阻断糖皮质激素诱导的NR3C1向细胞核转位。一致性实验结果显示，使用MK-2206抑制AKT1活性，可在T-ALL细胞系与原代患者样本中增强T-ALL细胞对糖皮质激素治疗的响应程度，从而在体外及体内环境中有效逆转糖皮质激素抵抗。上述研究结果支持开展AKT1抑制剂与糖皮质激素联合疗法治疗T-ALL的临床试验。研究设计：本研究共纳入228份T-ALL样本，其中117份为GSE26713数据集的重分析样本。