title: Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome.
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.
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Marjorie J
authors.initials: MJ
authors.lastname: Lindhurst
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Miranda R
authors.initials: MR
authors.lastname: Yourick
authors.affiliation: ArQule, Inc., Burlington, MA, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.affiliation: ArQule, Inc., Burlington, MA, USA.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Savage
authors.affiliation: ArQule, Inc., Burlington, MA, USA.
authors.forename: Dora
authors.initials: D
authors.lastname: Ferrari
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000077214:Becaplermin; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016715:Proteus Syndrome / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000631:Aminopyridines; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D051057:Proto-Oncogene Proteins c-akt; C000608559:Miransertib