Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy
A new retrospective study conducted by a vast international research partnership of 27 institutions suggests that a cancer drug already on the market could be used to treat certain children with Noonan syndrome who suffer from heart disease.
Noonan syndrome belongs to the large group of diseases called RASopathies and is a caused by genetic alterations that lead to disturbed development of several body parts, including for example short stature and peculiar facial features. Various complications can arise, particularly heart-related. Around one child in 2,500 is thought to carry the mutation, and of these, one in five will develop thickening of the heart muscle, called hypertrophic cardiomyopathy. This condition of the heart can lead to heart failure, rhythm disturbances, and even death if untreated. Currently available treatments are aimed at alleviating symptoms and managing complications, but none addresses the underlying disease causing problem.
The study analyzed medical information of 61 children with Noonan syndrome who suffered from severe hypertrophic cardiomyopathy. The patients studied were admitted to one of the 23 participating hospitals (10 countries) between 2000 and 2023 because they needed treatment of their heart failure or because they needed to undergo cardiac surgery, in which part of the thickened muscle is removed (septal myectomy). About half the patients received standard treatment, while the other comparable half also received a drug called trametinib as compassionate or off-label use. Trametinib inhibits the MEK (abbreviation for Mitogen-activated protein kinase) protein and is a drug that was developed as cancer treatment. MEK protein is also over-activated in the cells of children with Noonan syndrome, contributing to the pathological thickening of the heart wall.
The findings show that, over a three-year period, children who received the standard treatment alone had an 80% probability of undergoing surgery, a heart transplant or dying. The probability fell to 20% for children who were also treated with trametinib. Children that received additional trametinib over time suffered less from heart failure, their echocardiographic measurements improved, and their blood work showed a decrease in their abnormally elevated biomarkers.
Results of this large retrospective analysis provide evidence that MEK inhibitors have the potential to treat cardiac complications in children with Noonan syndrome.
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, Theoret Y, Bogarapu S, Dancea A, Handrup MM, Kemna M, Ojala T, Dham N, Dicke F, Friede T, Kaski JP, Gelb BD and Andelfinger G. Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy. JACC Basic Transl Sci. 2025;10:152-166.
Translated by Cordula Wolf and Corola Ossenkopp
Editorial to this article:
Hsu DT. Promising But Not Yet the Promised Land. JACC Basic Transl Sci. 2025;10:167-169.
New England Journal of Medicine Journal Watch Cardiology with a review by the Deputy Editor Mark Link:
https://www.jwatch.org/na58374/2025/01/29/mek-inhibition-children-with-rasopathy-associated