An Assessment of the Therapeutic Landscape for the Treatment of Heart Disease in the RASopathies

Abstract

The RAS/mitogen-activated protein kinase (MAPK) pathway controls a plethora of developmental and post-developmental processes. It is now clear that mutations in the RAS-MAPK pathway cause developmental diseases collectively referred to as the RASopathies. The RASopathies include Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome, neurofibromatosis type 1, and Costello syndrome. RASopathy patients exhibit a wide spectrum of congenital heart defects (CHD), such as valvular abnormalities and hypertrophic cardiomyopathy (HCM). Since the cardiovascular defects are the most serious and recurrent cause of mortality in RASopathy patients, it is critical to understand the pathological signaling mechanisms that drive the disease. Therapies for the treatment of HCM and other RASopathy-associated comorbidities have yet to be fully realized. Recent developments have shown promise for the use of repurposed antineoplastic drugs that target the RAS-MAPK pathway for the treatment of RASopathy-associated HCM. However, given the impact of the RAS-MAPK pathway in post-developmental physiology, establishing safety and evaluating risk when treating children will be paramount. As such insight provided by preclinical and clinical information will be critical. This review will highlight the cardiovascular manifestations caused by the RASopathies and will discuss the emerging therapies for treatment.

Keywords: Congenital heart disease; Noonan syndrome; RAS-MAPK signaling; RASopathies.

Fig. 1

Schematic of the RAS-MAPK pathway in HCM development. Ligand-stimulated membrane receptors (RTKs, GPCRs) and mechanical stress sensors (integrins) initiate HCM signal transduction through the RAS/MAPK pathway. Aberrant RAS/MAPK signaling converges on transcription factors that regulate gene expression in HCM pathogenesis

Fig. 2

Schematic of the RAS-MAPK pathway and RASopathy-associated syndromes. Syndromes are denoted with the protein in the pathway encoded by the causative mutated gene (bold). Small molecules for the treatment of RASopathy-associated CHD and their target inhibition are labeled (red). NS, Noonan syndrome; NSML, Noonan syndrome with multiple lentigines; NF1, neurofibromatosis 1; CS, Costello syndrome; CFCS, cardiofaciocutaneous syndrome