Abstract 19499: In vivo Efficacy of the AKT Inhibitor ARQ092 in Noonan Syndrome With Multiple Lentigines-Associated Hypertrophic Cardiomyopathy
Noonan Syndrome with Multiple Lentigines (NSML, formerly called 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) gene that encodes the SH2 domain-containing PTP-2 (SHP2). We generated knock-in mice harboring the PTPN11 mutation Y279C, one of the most common NSML alleles; these SHP2Y279C/+ mice recapitulated the human disorder, and developed hypertrophic cardiomyopathy (HCM) by 12 weeks of age. Moreover, heart and/or cardiomyocyte lysates from SHP2Y279C/+ mice exhibited increased basal and agonist-induced AKT and mTOR activities. The purpose of this study was to assess whether the cardiac defects in SHP2Y279C/+ mice were reversed by treatment with ARQ092, an AKT inhibitor in clinical trials for patients with PI3K/AKT-driven tumors or Proteus syndrome.
We obtained echocardiographs of SHP2Y279C/+ and WT littermates, either in the presence or absence of ARQ092 at 12, 14, and 16 weeks of age. SHP2Y279C/+ mice developed significant left ventricular hypertrophy, as indicated by decreased chamber dimension and increased posterior wall thickness compared with littermate controls which progressed over the course of the 4 week study. Treatment of SHP2Y279C/+mice with ARQ092 normalized the HCM as early as 2 weeks following treatment, with levels comparable to those in WT. No abnormal cardiac function was detected in hearts of WT mice, whether treated with vehicle or ARQ092. Interestingly, we observed an increase in fractional shortening (FS%) over time in the SHP2Y279C/+ mice, an effect of compensatory hypertrophy; this was not apparent in SHP2Y279C/+ mice treated with ARQ092, suggesting functional improvement upon treatment with the AKT inhibitor. SHP2Y279C/+ mice also showed trending normalization in HW/TL ratios as compared to WT, suggesting this drug may be a novel therapy for treatment of HCM in NSML. Mechanistic studies are currently underway.
Author Disclosures: V. Chandrasekhar: None. J. Wang: None. J. Cross: None. G. Abbadessa: None. Y. Yu: None. M.I. Kontaridis: None.
- © 2016 by American Heart Association, Inc.