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

Marjorie J Lindhurst,Yi Yu,Miranda R Yourick,Dora Ferrari,Ronald E Savage,Leslie G Biesecker

doi:10.1038/srep17162

Abstract

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.

Highlights

Proteus syndrome is characterized by progressive, mosaic, segmental overgrowth that can affect any organ or tissue in the body[1]
We showed that fibroblasts positive for the AKT1 E17K mutation had elevated phospho-AKT levels compared to mutation-negative cells when both were grown in serum-free medium[3]
PAKT levels were measured in single cell clones (SCC) that were heterozygous for the AKT1 E17K mutation or mutation-negative, and were grown in the presence or absence of serum (Fig. 1)

Summary

Introduction

Proteus syndrome is characterized by progressive, mosaic, segmental overgrowth that can affect any organ or tissue in the body[1] It is caused when a c.49G> A, p.Glu17Lys (hereafter referred to as AKT1 E17K) somatic activating mutation[2] in the serine/threonine kinase AKT1 occurs during development and results in an individual with both mutant and wild type cells[3]. ARQ 092 is a novel, orally bioavailable non-ATP competitive allosteric pan-AKT inhibitor It is highly selective for AKT1, AKT2, and AKT3 and has shown potent inhibition of AKT pathway signaling and tumor growth in mouse xenograft models explanted with cells harboring dysregulated AKT pathways[11]. These data support the clinical development of ARQ 092 in patients with Proteus syndrome, targeting this pathway as a novel treatment for this disease

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