Modulation of Glucocorticoid Resistance in Pediatric T-cell Acute Lymphoblastic Leukemia by Increasing BIM Expression with the PI3K/mTOR Inhibitor BEZ235.
Modulation of Glucocorticoid Resistance in Pediatric T-cell Acute Lymphoblastic Leukemia by Increasing BIM Expression with the PI3K/mTOR Inhibitor BEZ235.
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DOI：
10.1158/1078-0432.ccr-15-0114
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发表时间：
2016-02-01
期刊：
影响因子：
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通讯作者：
Kang MH
中科院分区：
文献类型：
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作者：
Hall CP;Reynolds CP;Kang MH
我们的研究目的是评估双PI3K/mTOR抑制剂BEZ235联合地塞米松治疗ALL的临床前治疗活性和作用机制。在ALL细胞系和异种移植模型中评估了BEZ235和地塞米松作为单一药物和联合药物的细胞毒性作用。采用免疫印迹、TaqMan RT-PCR、siRNA、免疫组织化学和免疫沉淀等方法评价BEZ235和地塞米松作用的潜在机制。双PI3K/mTOR抑制剂BEZ235抑制PI3K/AKT/mTOR通路，增强了地塞米松诱导的体外（连续细胞系和原代ALL培养）和体内全身T-ALL模型（包括患者来源的异种移植物）的抗白血病活性。通过抑制AKT1， BEZ235能够减轻AKT1介导的地塞米松诱导的凋亡通路的抑制，导致促凋亡的BCL-2蛋白BIM的表达增加。BEZ235下调MCL-1进一步通过增加可诱导凋亡的BIM量来调节地塞米松耐药，特别是在PTEN-null的T-ALL中，AKT的抑制仅部分克服了AKT诱导的BIM抑制。我们的数据支持进一步研究靶向PI3K/mTOR通路调节T-ALL糖皮质激素耐药的药物。
The aim of our study is to evaluate the preclinical therapeutic activity and mechanism of action of BEZ235, a dual PI3K/mTOR inhibitor, in combination with dexamethasone in ALL. The cytotoxic effects of BEZ235 and dexamethasone as single agents and in combination were assessed in a panel of ALL cell lines and xenograft models. The underlying mechanism of BEZ235 and dexamethasone was evaluated using immunoblotting, TaqMan RT-PCR, siRNA, immunohistochemistry and immunoprecipitation. Inhibition of the PI3K/AKT/mTOR pathway with the dual PI3K/mTOR inhibitor BEZ235 enhanced dexamethasone-induced anti-leukemic activity in in vitro (continuous cell lines and primary ALL cultures) and systemic in vivo models of T-ALL (including a patient-derived xenograft). Through inhibition of AKT1, BEZ235 was able to alleviate AKT1-mediated suppression of dexamethasone-induced apoptotic pathways leading to increased expression of the pro-apoptotic BCL-2 protein BIM. Downregulation of MCL-1 by BEZ235 further contributed to the modulation of dexamethasone resistance by increasing the amount of BIM available to induce apoptosis, especially in PTEN-null T-ALL where inhibition of AKT only partially overcame AKT-induced BIM suppression. Our data support the further investigation of agents targeting the PI3K/mTOR pathway to modulate glucocorticoid resistance in T-ALL.