Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy

Research output: Contribution to journal › Article › Research › peer review

Authors

  • Cordula M. Wolf
  • Martin Zenker
  • Olga Boleti
  • Gabrielle Norrish
  • Mark Russell
  • Joshua K. Meisner
  • David M. Peng
  • Terence Prendiville
  • Jake Kleinmahon
  • Paul F. Kantor
  • Danielle Gottlieb Sen
  • Derek G. Human
  • Peter Ewert
  • Marcus Krueger
  • Daniela Reber
  • Birgit Donner
  • Christopher Hart
  • Irena Odri Komazec
  • Stefan Rupp
  • Andreas Hahn
  • Anja Hanser
  • Michael Hofbeck
  • Jos M.T. Draaisma
  • Floris E.A. Udink ten Cate
  • Alessandro Mussa
  • Giovanni B. Ferrero
  • Laurence Vaujois
  • Marie Josée Raboisson
  • Marie Ange Delrue
  • Christopher Marquis
  • Yves Théoret
  • Soujanya Bogarapu
  • Adrian Dancea
  • Mette Moller Handrup
  • Mariska Kemna
  • Tiina Ojala
  • Niti Dham
  • Frank Dicke
  • Tim Friede
  • Juan Pablo Kaski
  • Bruce D. Gelb
  • Gregor Andelfinger

External Research Organisations

  • Technical University of Munich (TUM)
  • German Centre for Cardiovascular Research
  • ERN GUARD-Heart
  • Otto-von-Guericke University Magdeburg
  • University College London (UCL)
  • Great Ormond Street Hospital for Children NHS Trust
  • University of Michigan
  • Our Lady's Hospital for Sick Children
  • Ochsner Hospital for Children
  • University of Southern California
  • Johns Hopkins University
  • University of British Columbia
  • München Klinik Bogenhausen
  • University of Basel
  • University of Bonn
  • Innsbruck Medical University
  • University Hospital Gießen and Marburg
  • Justus Liebig University Giessen
  • University of Tübingen
  • Radboud University Nijmegen (RU)
  • University of Turin
  • Universite Laval
  • University of Montreal
  • University of Illinois at Chicago
  • McGill University Health Center
  • Aarhus University
  • Seattle Children's Hospital
  • University of Helsinki
  • Children's National Medical Center
  • University of Calgary
  • University of Göttingen
  • German Center for Child and Adolescent Health (DZKJ)
  • Icahn School of Medicine at Mount Sinai (ISMMS)
View graph of relations

Details

Original languageEnglish
Pages (from-to)152-166
Number of pages15
JournalJACC: Basic to Translational Science
Volume10
Issue number2
Early online date4 Dec 2024
Publication statusPublished - Feb 2025
Externally publishedYes

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

    childhood cardiomyopathy, MEK inhibition, Noonan syndrome spectrum, RAS/MAPK signaling, RASopathies, survival

ASJC Scopus subject areas

Cite this

Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy. / Wolf, Cordula M.; Zenker, Martin; Boleti, Olga et al.
In: JACC: Basic to Translational Science, Vol. 10, No. 2, 02.2025, p. 152-166.

Research output: Contribution to journal › Article › Research › peer review

Wolf, CM, Zenker, M, Boleti, O, Norrish, G, Russell, M, Meisner, JK, Peng, DM, Prendiville, T, Kleinmahon, J, Kantor, PF, Gottlieb Sen, D, Human, DG, Ewert, P, Krueger, M, Reber, D, Donner, B, Hart, C, Odri Komazec, I, Rupp, S, Hahn, A, Hanser, A, Hofbeck, M, Draaisma, JMT, Udink ten Cate, FEA, Mussa, A, Ferrero, GB, Vaujois, L, Raboisson, MJ, Delrue, MA, Marquis, C, Théoret, Y, Bogarapu, S, Dancea, A, Handrup, MM, Kemna, M, Ojala, T, Dham, N, Dicke, F, Friede, T, Kaski, JP, Gelb, BD & Andelfinger, G 2025, 'Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy', JACC: Basic to Translational Science, vol. 10, no. 2, pp. 152-166. https://doi.org/10.1016/j.jacbts.2024.10.002
Wolf, C. M., Zenker, M., Boleti, O., Norrish, G., Russell, M., Meisner, J. K., Peng, D. M., Prendiville, T., Kleinmahon, J., Kantor, P. F., Gottlieb Sen, D., Human, D. G., Ewert, P., Krueger, M., Reber, D., Donner, B., Hart, C., Odri Komazec, I., Rupp, S., ... Andelfinger, G. (2025). Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy. JACC: Basic to Translational Science, 10(2), 152-166. https://doi.org/10.1016/j.jacbts.2024.10.002
Wolf CM, Zenker M, Boleti O, Norrish G, Russell M, Meisner JK et al. Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy. JACC: Basic to Translational Science. 2025 Feb;10(2):152-166. Epub 2024 Dec 4. doi: 10.1016/j.jacbts.2024.10.002
Wolf, Cordula M. ; Zenker, Martin ; Boleti, Olga et al. / Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy. In: JACC: Basic to Translational Science. 2025 ; Vol. 10, No. 2. pp. 152-166.
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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.",
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AU - Wolf, Cordula M.

AU - Zenker, Martin

AU - Boleti, Olga

AU - Norrish, Gabrielle

AU - Russell, Mark

AU - Meisner, Joshua K.

AU - Peng, David M.

AU - Prendiville, Terence

AU - Kleinmahon, Jake

AU - Kantor, Paul F.

AU - Gottlieb Sen, Danielle

AU - Human, Derek G.

AU - Ewert, Peter

AU - Krueger, Marcus

AU - Reber, Daniela

AU - Donner, Birgit

AU - Hart, Christopher

AU - Odri Komazec, Irena

AU - Rupp, Stefan

AU - Hahn, Andreas

AU - Hanser, Anja

AU - Hofbeck, Michael

AU - Draaisma, Jos M.T.

AU - Udink ten Cate, Floris E.A.

AU - Mussa, Alessandro

AU - Ferrero, Giovanni B.

AU - Vaujois, Laurence

AU - Raboisson, Marie Josée

AU - Delrue, Marie Ange

AU - Marquis, Christopher

AU - Théoret, Yves

AU - Bogarapu, Soujanya

AU - Dancea, Adrian

AU - Handrup, Mette Moller

AU - Kemna, Mariska

AU - Ojala, Tiina

AU - Dham, Niti

AU - Dicke, Frank

AU - Friede, Tim

AU - Kaski, Juan Pablo

AU - Gelb, Bruce D.

AU - Andelfinger, Gregor

N1 - Publisher Copyright: © 2025 The Authors

PY - 2025/2

Y1 - 2025/2

N2 - 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.

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KW - MEK inhibition

KW - Noonan syndrome spectrum

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