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. 2017 Jun 5;12(6):e0178905.
doi: 10.1371/journal.pone.0178905. eCollection 2017.

In Vivo Efficacy of the AKT Inhibitor ARQ 092 in Noonan Syndrome With Multiple Lentigines-Associated Hypertrophic Cardiomyopathy

Free PMC article

In Vivo Efficacy of the AKT Inhibitor ARQ 092 in Noonan Syndrome With Multiple Lentigines-Associated Hypertrophic Cardiomyopathy

Jianxun Wang et al. PLoS One. .
Free PMC article


Noonan Syndrome with Multiple Lentigines (NSML, formerly LEOPARD syndrome) is an autosomal dominant "RASopathy" disorder manifesting in congenital heart disease. Most cases of NSML are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11), encoding the SH2 domain-containing PTP-2 (SHP2) protein. We previously generated knock-in mice harboring the PTPN11 mutation Y279C, one of the most common NSML alleles; these now-termed SHP2Y279C/+ mice recapitulate the human disorder and develop hypertrophic cardiomyopathy (HCM) by 12 weeks of age. Functionally, heart and/or cardiomyocyte lysates from SHP2Y279C/+ mice exhibit increased basal and agonist-induced AKT and mTOR activities. Here, we sought to determine whether we could reverse the hypertrophy in SHP2Y279C/+ mice using ARQ 092, an oral and selective allosteric AKT inhibitor currently in clinical trials for patients with PI3K/AKT-driven tumors or Proteus syndrome. We obtained echocardiographs of SHP2Y279C/+ and wildtype (SHP2+/+) littermates, either in the presence or absence of ARQ 092 at 12, 14, and 16 weeks of age. While SHP2Y279C/+ mice developed significant left ventricular hypertrophy by 12 weeks, as indicated by decreased chamber dimension and increased posterior wall thickness, treatment of SHP2Y279C/+ mice with ARQ 092 normalized the hypertrophy in as early as 2 weeks following treatment, with hearts comparable in size to those in wildtype (SHP2+/+) mice. In addition, we observed an increase in fractional shortening (FS%) in SHP2Y279C/+ mice, an effect of increased compensatory hypertrophy, which was not apparent in SHP2Y279C/+ mice treated with ARQ 092, suggesting functional improvement of HCM upon treatment with the AKT inhibitor. Finally, we found that ARQ 092 specifically inhibited AKT activity, as well as its downstream effectors, PRAS and S6RP in NSML mice. Taken together, these data suggest ARQ 092 may be a promising novel therapy for treatment of hypertrophy in NSML patients.

Conflict of interest statement

Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: GA, YY, and BS are employees of ArQule, Inc, the company that provided the inhibitor used in this study and which funded the project herein. This does not alter our adherence to PLOS ONE policies on sharing data and materials.


Fig 1
Fig 1. ARQ 092—Treated SHP2Y279C/+ hearts have normalized AKT/mTOR signaling.
Mouse heart lysates were generated from wild-type (SHP2+/+) and NSML (SHP2Y279C/+) littermates subjected to either vehicle or ARQ 092 treatment (100mg/kg/day orally) for 4 weeks, starting at 12 weeks of age. The heart lysates were immunoblotted with anti—phospho-AKT, anti—phospho-S6RP and anti-phospho-PRAS40, as indicated, followed by anti-AKT, anti-S6RP, and anti-PRAS40, respectively, to control for loading. Parallel experimental samples were blotted with anti-SHP2 or anti-GAPDH to determine expression levels of these proteins. Quantification of data (n = 3–7 mice/group) is shown to the right of each representative Western blot. Data represent mean ± SEM; *P < 0.05, 2-way ANOVA on ranked data, with Bonferroni post hoc test when ANOVA was significant.
Fig 2
Fig 2. Treatment with ARQ 092 reduces cardiac hypertrophy and normalizes heart size in NSML.
16 week-old SHP2 wild-type (SHP2+/+) and NSML (SHP2Y279C/+) littermates were treated with either vehicle or ARQ 092 AKT inhibitor (of 100mg/kg/day orally) for 4 weeks, beginning at 12 weeks of age. (A). Representative transverse cross-section of whole hearts (scale bar 1mm) and H&E- and Reticulin-stained sections (scale bar 50 microns); enlarged inset images represent the indicated areas (scale bar 50 microns). Total heart weight (B) and cardiomyocyte cell size (C), as measured from reticulin-stained heart cross-sections. *P < 0.05, where P values were derived from 2-way ANOVA on ranked data, with Bonferroni post hoc test when ANOVA was significant; n = 3–7 mice/group.
Fig 3
Fig 3. SHP2Y279C/+ hearts treated with ARQ 092 have improved cardiac function.
Echocardiography was used to analyze the cardiac function in SHP2+/+ and SHP2Y279C/+ mice, either vehicle or ARQ 092 treated for 4 weeks, starting at 12 weeks of age. (A) LVIDd, (B) LVPWd, (C) SV (D) IVSs, (E) IVSd, and (F) FS% parameters were measured Data represent mean ± SEM. *P < 0.05, where P values were derived from from 2-way ANOVA on ranked data, with Bonferroni post hoc test when ANOVA was significant; n = 3–7 mice/group. LVIDd, left ventricular chamber dimension in diastole; LVPWd, left ventricular posterior wall thickness in diastole; SV, stroke volume; IVSs, intraventricular septal diameter in systole; IVSd, intraventricular septal diameter in diastole; FS%, fractional shortening.

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