Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy

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

doi:10.1016/j.jacbts.2024.10.002

Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy

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 HahnAnja 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^*

^*Corresponding author for this work

Department of Clinical Medicine - Department of Paediatrics

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

4 Citations (Scopus)

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.

Original language	English
Journal	JACC: Basic to translational science
Volume	10
Issue	2
Pages (from-to)	152-166
Number of pages	15
ISSN	2452-302X
DOIs	https://doi.org/10.1016/j.jacbts.2024.10.002
Publication status	Accepted/In press - Feb 2025

Keywords

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

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10.1016/j.jacbts.2024.10.002Licence: CC BY

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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. (Accepted/In press). 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

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title = "Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy",

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",

author = "Wolf, {Cordula M.} and Martin Zenker and Olga Boleti and Gabrielle Norrish and Mark Russell and Meisner, {Joshua K.} and Peng, {David M.} and Terence Prendiville and Jake Kleinmahon and Kantor, {Paul F.} and {Gottlieb Sen}, Danielle and Human, {Derek G.} and Peter Ewert and Marcus Krueger and Daniela Reber and Birgit Donner and Christopher Hart and {Odri Komazec}, Irena and Stefan Rupp and Andreas Hahn and Anja Hanser and Michael Hofbeck and Draaisma, {Jos M.T.} and {Udink ten Cate}, {Floris E.A.} and Alessandro Mussa and Ferrero, {Giovanni B.} and Laurence Vaujois and Raboisson, {Marie Jos{\'e}e} and Delrue, {Marie Ange} and Christopher Marquis and Yves Th{\'e}oret and Soujanya Bogarapu and Adrian Dancea and Handrup, {Mette Moller} and Mariska Kemna and Tiina Ojala and Niti Dham and Frank Dicke and Tim Friede and Kaski, {Juan Pablo} and Gelb, {Bruce D.} and Gregor Andelfinger",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = feb,

doi = "10.1016/j.jacbts.2024.10.002",

language = "English",

volume = "10",

pages = "152--166",

journal = "JACC: Basic to translational science",

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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

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/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy

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

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.

AB - 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.

KW - childhood cardiomyopathy

KW - MEK inhibition

KW - Noonan syndrome spectrum

KW - RAS/MAPK signaling

KW - RASopathies

KW - survival

UR - http://www.scopus.com/inward/record.url?scp=85217139628&partnerID=8YFLogxK

U2 - 10.1016/j.jacbts.2024.10.002

DO - 10.1016/j.jacbts.2024.10.002

M3 - Journal article

C2 - 40131150

AN - SCOPUS:85217139628

SN - 2452-302X

VL - 10

SP - 152

EP - 166

JO - JACC: Basic to translational science

JF - JACC: Basic to translational science

IS - 2

ER -

Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy

Abstract

Keywords

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