Novel therapeutic perspectives in Noonan syndrome and RASopathies

Abstract

AbstractNoonan syndrome belongs to the family of RASopathies, a group of multiple congenital anomaly disorders caused by pathogenic variants in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway. Collectively, all these pathogenic variants lead to increased RAS/MAPK activation. The better understanding of the molecular mechanisms underlying the different manifestations of NS and RASopathies has led to the identification of molecular targets for specific pharmacological interventions. Many specific agents (e.g. SHP2 and MEK inhibitors) have already been developed for the treatment of RAS/MAPK-driven malignancies. In addition, other molecules with the property of modulating RAS/MAPK activation are indicated in non-malignant diseases (e.g. C-type natriuretic peptide analogues in achondroplasia or statins in hypercholesterolemia).  Conclusion: Drug repositioning of these molecules represents a challenging approach to treat or prevent medical complications associated with RASopathies. What is Known:• Noonan syndrome and related disorders are caused by pathogenic variants in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway, resulting in increased activation of this pathway.• This group of disorders is now known as RASopathies and represents one of the largest groups of multiple congenital anomaly diseases known. What is New:• The identification of pathophysiological mechanisms provides new insights into the development of specific therapeutic strategies, in particular treatment aimed at reducing RAS/MAPK hyperactivation.• Drug repositioning of specific agents already developed for the treatment of malignant (e.g. SHP2 and MEK inhibitors) or non-malignant diseases (e.g. C-type natriuretic peptide analogues in achondroplasia or statins in hypercholesterolaemia) represents a challenging approach to the treatment of RASopathies.