Low-dose Dasatinib Ameliorates Hypertrophic Cardiomyopathy in Noonan Syndrome with Multiple Lentigines

Cardiovasc Drugs Ther. 2022 Aug;36(4):589-604. doi: 10.1007/s10557-021-07169-z. Epub 2021 Mar 10.

Abstract

Purpose: Noonan syndrome with multiple lentigines (NSML) is an autosomal dominant disorder presenting with hypertrophic cardiomyopathy (HCM). Up to 85% of NSML cases are caused by mutations in the PTPN11 gene that encodes for the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2). We previously showed that low-dose dasatinib protects from the development of cardiac fibrosis in a mouse model of NSML harboring a Ptpn11Y279C mutation. This study is performed to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties of a low-dose of dasatinib in NSML mice and to determine its effectiveness in ameliorating the development of HCM.

Methods: Dasatinib was administered intraperitoneally into NSML mice with doses ranging from 0.05 to 0.5 mg/kg. PK parameters of dasatinib in NSML mice were determined. PD parameters were obtained for biochemical analyses from heart tissue. Dasatinib-treated NSML mice (0.1 mg/kg) were subjected to echocardiography and assessment of markers of HCM by qRT-PCR. Transcriptome analysis was performed from the heart tissue of low-dose dasatinib-treated mice.

Results: Low-dose dasatinib exhibited PK properties that were linear across doses in NSML mice. Dasatinib treatment of between 0.05 and 0.5 mg/kg in NSML mice yielded an exposure-dependent inhibition of c-Src and PZR tyrosyl phosphorylation and inhibited AKT phosphorylation. We found that doses as low as 0.1 mg/kg of dasatinib prevented HCM in NSML mice. Transcriptome analysis identified differentially expressed HCM-associated genes in the heart of NSML mice that were reverted to wild type levels by low-dose dasatinib administration.

Conclusion: These data demonstrate that low-dose dasatinib exhibits desirable therapeutic PK properties that is sufficient for effective target engagement to ameliorate HCM progression in NSML mice. These data demonstrate that low-dose dasatinib treatment may be an effective therapy against HCM in NSML patients.

Keywords: Hypertrophic cardiomyopathy; Noonan syndrome with multiple lentigines; Protein tyrosine phosphatases; RASopathy; Tyrosine kinase inhibitor.

MeSH terms

  • Animals
  • Cardiomyopathy, Hypertrophic* / drug therapy
  • Cardiomyopathy, Hypertrophic* / genetics
  • Dasatinib / pharmacology
  • Dasatinib / therapeutic use
  • Disease Models, Animal
  • LEOPARD Syndrome* / drug therapy
  • LEOPARD Syndrome* / genetics
  • LEOPARD Syndrome* / metabolism
  • Mice
  • Mutation

Substances

  • Dasatinib