Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome.
Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome.
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DOI：
10.1038/srep17162
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发表时间：
2015-12-11
影响因子：
4.6
通讯作者：
Biesecker LG
中科院分区：
文献类型：
--
作者：
Lindhurst MJ;Yourick MR;Yu Y;Savage RE;Ferrari D;Biesecker LG
AKT1，c.49G>A，pGlu17Lys中的体细胞激活突变导致突变阳性细胞中AKT信号传导升高，这是马赛克过度生长状况，变形综合征的原因。ARQ 092是一种正在开发的用于癌症治疗的变构泛AKT抑制剂。我们测试了这种药物抑制变形综合征患者细胞和组织中AKT信号传导的功效。ARQ 092在短短两小时内以浓度依赖性方式减少AKT和AKT下游靶标的磷酸化。虽然AKT信号传导被ARQ 092处理抑制，但细胞通过与未处理细胞成比例地增加pAKT水平来保持其响应生长因子刺激的能力。在足以降低AKT信号传导的浓度下，观察到细胞活力几乎没有降低。这些结果表明，ARQ 092可以抑制AKT信号传导，并保证进一步开发作为变形综合征患者的治疗选择。
A somatic activating mutation in AKT1, c.49G>A, pGlu17Lys, that results in elevated AKT signaling in mutation-positive cells, is responsible for the mosaic overgrowth condition, Proteus syndrome. ARQ 092 is an allosteric pan-AKT inhibitor under development for treatment in cancer. We tested the efficacy of this drug for suppressing AKT signaling in cells and tissues from patients with Proteus syndrome. ARQ 092 reduced phosphorylation of AKT and downstream targets of AKT in a concentration-dependent manner in as little as two hours. While AKT signaling was suppressed with ARQ 092 treatment, cells retained their ability to respond to growth factor stimulation by increasing pAKT levels proportionally to untreated cells. At concentrations sufficient to decrease AKT signaling, little reduction in cell viability was seen. These results indicate that ARQ 092 can suppress AKT signaling and warrants further development as a therapeutic option for patients with Proteus syndrome.