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. 2025 Feb;10(2):152-166.
doi: 10.1016/j.jacbts.2024.10.002. Epub 2024 Dec 4.

Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy

Cordula M Wolf  1 , Martin Zenker  2 , Olga Boleti  3 , Gabrielle Norrish  3 , Mark Russell  4 , Joshua K Meisner  4 , David M Peng  4 , Terence Prendiville  5 , Jake Kleinmahon  6 , Paul F Kantor  7 , Danielle Gottlieb Sen  8 , Derek G Human  9 , Peter Ewert  1 , Marcus Krueger  10 , Daniela Reber  10 , Birgit Donner  11 , Christopher Hart  12 , Irena Odri Komazec  13 , Stefan Rupp  14 , Andreas Hahn  15 , Anja Hanser  16 , Michael Hofbeck  16 , Jos M T Draaisma  17 , Floris E A Udink Ten Cate  17 , Alessandro Mussa  18 , Giovanni B Ferrero  19 , Laurence Vaujois  20 , Marie-Josée Raboisson  21 , Marie-Ange Delrue  21 , Christopher Marquis  21 , Yves Théoret  21 , Soujanya Bogarapu  22 , Adrian Dancea  23 , Mette Moller Handrup  24 , Mariska Kemna  25 , Tiina Ojala  26 , Niti Dham  27 , Frank Dicke  28 , Tim Friede  29 , Juan Pablo Kaski  3 , Bruce D Gelb  30 , Gregor Andelfinger  31
Affiliations

Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy

Cordula M Wolf et al. JACC Basic Transl Sci. 2025 Feb.

Abstract

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.

Keywords: MEK inhibition; Noonan syndrome spectrum; RAS/MAPK signaling; RASopathies; childhood cardiomyopathy; survival.

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Conflict of interest statement

Funding Support and Author Disclosures Dr Wolf is supported by the Gerd-Killian Award of Deutsche Herzstiftung, Deutsches Zentrum für Herz-Kreislauf-Forschung (German Center for Cardiovascular Research) and by Bundesministerium für Bildung und Forschung (German Ministry of Education and Research); and is member of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart. Dr Zenker has received funding from Bundesministerium für Bildung und Forschung as part of national and European research networks on RASopathies (German Network for RASopathy Research; FKZ: 01GM1902A) and European Joint Programme on Rare Disease funding (NSEuroNet consortium; FKZ: 01GM1921A). Several authors of this publication are members of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, which is funded by the EU4Health program of the European Union, under grant agreement 101085231 (National Children’s Research Centre). Dr Norrish is supported by the Association for European Paediatric and Congenital Cardiology and Great Ormond Street Hospital Charity. Dr Kaski is supported by a Medical Research Council Clinical Academic Partnership Award and by the British Heart Foundation, Action Medical Research, Max's Foundation, and the Great Ormond Street Hospital Children's Charity. Dr Gelb is supported by a grant from the National Institutes of Health (HL135742). Dr Andelfinger is supported by the Banque Nationale Research Excellence Chair in Cardiovascular Genetics. None of the sponsors or funders had any role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; and in the preparation, review, or approval of the manuscript. Dr Wolf has received honoraria from Novo Nordisk and Bristol Myers Squibb; is a consultant for Bristol Myers Squibb, Rocket Pharmaceuticals, Day One Biopharmaceuticals, BioMarin Pharmaceuticals, Adrenomed, and Pliant Therapeutics. Dr Zenker has received honoraria: Novo Nordisk; and is a consultant or advisory board member for Day One Biopharmaceuticals, Novo Nordisk, and Novartis. Dr Friede has received personal fees from Actimed, Aslan, Bayer, Biosense Webster, Bristol Myers Squibb, CSL Behring, Enanta, Fresenius Kabi, Galapagos, Immunic, IQVIA, Janssen, Johnson & Johnson Medical, KyowaKirin, LivaNova, Minoryx, Novartis, RECARDIO, Recordati, Relaxera, Roche, Servier, Viatris, VICO Therapeutics, and Vifor for statistical consultancies, including data monitoring committees, all outside the submitted work. Dr Kaski has received honoraria from Novo Nordisk; and is a consultant for Novo Nordisk. Dr Gelb is a named inventor on issued patents related to PTPN11, SHOC2, RAF1, and SOS1 mutations. The Icahn School of Medicine at Mount Sinai licensed the patents to several diagnostics companies (Correlegan, GeneDx, LabCorp, and Prevention Genetics) and has received royalty payments, some of which are distributed to Dr Gelb. Dr Gelb was the recipient of a sponsored research agreement from Onconova Therapeutics; and was a consultant for Day One Biopharmaceuticals and BioMarin Pharmaceuticals. Dr Andelfinger is a consultant for Day One Biopharmaceuticals and BioMarin Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Clinical Outcomes During Follow-Up of Retrospective Cohort Analysis: Kaplan-Meier Curves for Primary and Secondary Endpoints (A) Time-to-event endpoints displayed as Kaplan-Meier curve for the primary composite endpoint of cardiac surgery for outflow tract obstruction or heart transplantation or death; product-limit survival estimates with number of subjects at risk and 95% Hall-Wellner bands; differences between groups are reported as HRs with 95% CIs and were tested using log-rank tests. Time 0 reflects the baseline time point when meeting inclusion criteria and admission to hospital. (B) Cumulative incidence function (Aalen-Johansen estimator) with 95% confidence limits for the secondary endpoint of cardiac surgery for outflow tract resection with death and heart transplantation as competing events; differences between groups are reported as HRs with 95% CIs and were tested using Gray’s test considering competing event analyses. Time 0 reflects the baseline time point when meeting inclusion criteria and admission to hospital. (C) Time-to-event endpoints displayed as Kaplan-Meier curve for the secondary endpoint of heart transplantation or death or transplantation; product-limit survival estimates with number of subjects at risk and 95% Hall-Wellner bands; differences between groups are reported as HRs with 95% CIs and were tested using log-rank tests. Time 0 reflects the baseline time point when meeting inclusion criteria and admission to hospital. (D) Time-to-event endpoints displayed as Kaplan-Meier curve for the secondary endpoint of heart transplantation or death in the subgroup of critically ill patients presenting in severe heart failure (Ross class IV; n = 16); product-limit survival estimates with number of subjects at risk and 95% Hall-Wellner bands; differences between groups are reported as HRs with 95% CIs and were tested using log-rank tests. Time 0 reflects the baseline time point when meeting inclusion criteria and admission to hospital. MEKi = mitogen-activated protein kinase kinase inhibition.
Figure 2
Figure 2
Clinical Outcomes During Follow-Up: Ross Classification and Consideration for Cardiac Surgery for Outflow Tract Resection After the Initiation of MEKi Treatment (A) Ross classification over time in patients in the mitogen-activated protein kinase kinase inhibition (MEKi) group (n = 30). Baseline timepoint reflects clinical status when meeting inclusion criteria and admission to hospital; Pearson chi-square P < 0.001. (B) Consideration for cardiac surgery for outflow tract resection according to current guidelines over time in patients in the MEKi group (n = 30). Baseline timepoint reflects clinical status when meeting inclusion criteria and admission to hospital; Pearson chi-square P < 0.001.
Figure 3
Figure 3
Effect of Treatment on Imaging and Proposed Mechanism of Action Transthoracic echocardiographic measurements of a 8.5-year-old patient carrying a pathogenic RAF1 mutation before (A to F) and after (G to L) 6 months treatment with the MEK inhibitor trametinib: (A and G): parasternal long axis, (B and H): m-mode; (C and I): apical five-chamber view; (D and J): continuous-wave Doppler through the left ventricular outflow tract on apical five-chamber view; (E and K): pulse-wave Doppler over mitral valve on apical four-chamber view; (F and L): septal pulse wave tissue Doppler on apical four-chamber view; decreased maximal end-diastolic myocardial wall thickness z-score (pretreatment 4.7, A and B; posttreatment 3.2, G and H) and increased end-diastolic left ventricular diameter z-scores (pretreatment −8, A and B; posttreatment −2.7, G and H); decrease in peak left ventricular outflow tract gradient from 88 mm Hg pretreatment (C and D) to 25 mm Hg posttreatment (I and J); improvement of diastolic function variables (pretreatment mitral valve E-to-A ratio 0.7, septal E-to-É 30, E and F; posttreatment mitral valve E-to-A ratio 1.0, septal E/É 20, K and L); (M): hypothesis of mechanism of action of small molecule therapies in patients with RASopathies and cardiomyopathy.
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