Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome

被引:52
作者
Lindhurst, Marjorie J. [1 ]
Yourick, Miranda R. [1 ]
Yu, Yi [2 ]
Savage, Ronald E. [2 ]
Ferrari, Dora [2 ]
Biesecker, Leslie G. [1 ]
机构
[1] NHGRI, NIH, Bethesda, MD 20892 USA
[2] ArQule Inc, Burlington, MA USA
关键词
MUTATION; DOMAIN; S6;
D O I
10.1038/srep17162
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页数:12
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