MAPK and mTOR Inhibition Improves Childhood RASopathy-Associated Hypertrophic Cardiomyopathy

Background: To evaluate the benefit of mutation-specific small molecule inhibitors of target of rapamycin (mTORi) or MAPK kinase (MEKi) in RAS-CM patients with severe pediatric-onset cardiomyopathy associated with distinct germline mutations in RAS/mitogen-activated protein kinase (MAPK) pathway (RAS-CM).

Method: Retrospective case–control analysis on 33 children with progressive RAS-CM receiving off-label or compassionate use mTORi and/or MEKi in addition to standard therapies (“treatment group”) and 40 age-, gender-, genotype- and disease-matched natural history patients (“control group”) in 21 European, North American, and British centers.

Results: Over a follow-up period of 3,200 patient-months, 67% of critically ill patients presenting in severe heart failure survived in the treatment versus none in the control group (p = 0.013). Transplant-free survival without undergoing surgical outflow tract resection was 79% in the treatment compared to 20% in the controls (p < 0.001). From baseline to last follow-up time point, there was a greater decrease in heart failure classification and myocardial wall thickness Z-score measured on echocardiography in treatment compared to control cases (median [IQR] change in Ross classification −2 [−2; −1] vs. −1 [−1.5; −0.5], p = 0.024; and in myocardial wall thickness −1.2 [−2.5; −0.1] vs. −0.7 [−0.9; 0.5], p = 0.027). Skin and mucous membranes were the most common organs affected by side effects, requiring cessation or reduction of therapy in 27% of patients. No life-threatening adverse events related to mTORi or MEKi were observed.

Conclusion: Selected RASopathy patients may benefit from novel mechanism-informed therapeutics targeting the RAS/MAPK pathway. Clinical trials are needed to substantiate the findings reported in this retrospective case-control analysis.

Publication History

Article published online:
28 January 2023