Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy

Abstract

• RAS/MAPK variants cause infant hypertrophic cardiomyopathy, increasing morbidity. • Hyperactivated pathway inhibition improves cardiomyopathy in RASopathy mouse models. • Retrospective study: 30 children on trametinib vs 31 on standard care for cardiomyopathy. • Trametinib significantly reduced death, transplant, and cardiac surgery risk. • Trametinib showed no severe adverse events; frequent skin and mucous side effects noted. There is an unmet medical need to treat patients with severe hypertrophic cardiomyopathy leading to heart failure and death in children carrying pathogenic activating variants in the RAS/mitogen-activated protein kinase pathway. A retrospective analysis of 61 patients provides evidence for decreased mortality and morbidity with improved cardiac status in patients with RASopathy with severe hypertrophic cardiomyopathy receiving mitogen-activated protein kinase kinase inhibition (n = 30) vs those with standard-of-care treatment (n = 31). Side effects were not life threatening and were manageable. The data presented suggest that personalized therapies targeting underlying signaling pathway abnormalities might be effective in critically ill patients with RASopathy warranting clinical investigation.