AKT/mTOR and MAPK Inhibition Improves Childhood RASopathic Cardiomyopathy

Background: RASopathies are a spectrum of pleomorphic syndromic disorders and caused by germline mutations in the RAS/mitogen-activated protein kinase (MAPK) pathway. They cause progressive RASopathy-associated cardiomyopathy (RAS-CM) for which no preventive or curative therapies exist. Young infants presenting with heart failure suffer from high mortality. RAS-CM presenting later in life is morbid with increased risk for sudden cardiac death or cardiac transplantation. Animal studies and limited case reports have suggested that small molecule inhibitors of target of rapamycin (mTOR) or mitogen-activated protein kinase kinase (MEK), pathways activated in certain RASopathies, are beneficial. The aim of this study is to report on 25 patients from Europe and North America with progressive and/or life-threatening RAS-CM in whom we initiated off-label or compassionate inhibition of mTOR or MEK after exhaustion of standard therapies.

Method: This study was done by retrospective data collection.

Results: Over a follow-up period of 296 patient-months (median, 5.5 months; range, 1.5–50), we observed increased transplant-free survival in critically ill patients <6 months of age treated with mTORi and/or MEKi as compared with that from natural history studies (75 vs. 39%, p = 0.031). Freedom from surgical intervention was 52% (11 of 21 patients in whom surgical outflow tract resection was indicated), and clinically meaningful improvement (greater than 20% from baseline) in 50% or more of preselected cardiac outcome variables occurred in 18 of 25 patients (72%) undergoing mTORi and/or MEKi treatment. No life-threatening adverse events related to mTORi or MEKi occurred.

Conclusion: These data suggest that selected RASopathy patients may benefit from mechanism-informed therapeutics guided by the biological understanding of cardiac pathology in this disease spectrum.

Publication History

Article published online:
12 February 2022