Succesful MEK-inhibition of severe hypertrophic cardiomyopathy in RIT1-related Noonan Syndrome

Leegaard, Anne; Gregersen, Pernille Axel; Nielsen, Trine Ø.; Bjerre, Jesper Vandborg; Handrup, Mette Møller

doi:10.1016/j.ejmg.2022.104630

Cited by 13 publications

(13 citation statements)

References 13 publications

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“…Case reports of off-label use of MEK inhibitors in infants with Noonan syndrome have demonstrated regression of myocyte hypertrophy and LVOT obstruction with amelioration of symptoms. 30 , 31 , 32 These early reports suggest a potential avenue of medical management of obstructive HCM in patients with RASopathies.…”

Section: Discussionmentioning

confidence: 99%

Long-term outcomes of surgery for obstructive hypertrophic cardiomyopathy in a pediatric cohort

Nguyen,

Chung,

Vinogradsky

et al. 2023

JTCVS Open

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Section: Discussionmentioning

confidence: 99%

Long-term outcomes of surgery for obstructive hypertrophic cardiomyopathy in a pediatric cohort

Nguyen,

Chung,

Vinogradsky

et al. 2023

JTCVS Open

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“…Here, we demonstrate that treatment of RIT1 M90I mice with the U.S. Food and Drug Administration–approved MEK1/MEK2 inhibitor trametinib (GSK1120212) ameliorated cardiac tissue overgrowth, suggesting that targeting the MAPK pathway may be an effective therapeutic strategy in NS patients with mutant RIT1. Off-label trametinib treatment was recently shown to reverse myocardial hypertrophy in three children with RIT1 NS ( 46 , 47 ). However, trametinib has been reported to induce substantial levels of toxicity in other disease contexts ( 48 , 49 ), highlighting the need for further preclinical work to address optimal dosing and treatment windows, response to different MEK inhibitors, and efficacy of upstream RAS inhibition to alleviate the cardiac and extracardiac RIT1 phenotype.…”

Section: Discussionmentioning

confidence: 99%

RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome–associated cardiac hypertrophy

et al. 2023

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RIT1 is a RAS guanosine triphosphatase (GTPase) that regulates different aspects of signal transduction and is mutated in lung cancer, leukemia, and in the germline of individuals with Noonan syndrome. Pathogenic RIT1 proteins promote mitogen-activated protein kinase (MAPK) hyperactivation; however, this mechanism remains poorly understood. Here, we show that RAF kinases are direct effectors of membrane-bound mutant RIT1 necessary for MAPK activation. We identify critical residues in RIT1 that facilitate interaction with membrane lipids and show that these are necessary for association with RAF kinases and MAPK activation. Although mutant RIT1 binds to RAF kinases directly, it fails to activate MAPK signaling in the absence of classical RAS proteins. Consistent with aberrant RAF/MAPK activation as a driver of disease, we show that pathway inhibition alleviates cardiac hypertrophy in a mouse model of RIT1 mutant Noonan syndrome. These data shed light on the function of pathogenic RIT1 and identify avenues for therapeutic intervention.

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“…Here, we demonstrate that treatment of RIT1 M90I mice with the FDA-approved MEK1/2 inhibitor trametinib (GSK1120212) ameliorated cardiac tissue overgrowth, suggesting that targeting the MAPK pathway may be an effective therapeutic strategy in NS patients with mutant RIT1. Indeed, off-label trametinib treatment was recently shown to reverse myocardial hypertrophy in three children with RIT1 NS ( 43, 44 ). However, trametinib has been reported to induce significant levels of toxicity in other disease contexts ( 45, 46 ), highlighting the need for further pre-clinical work to address optimal dosing and treatment windows, response to different MEK inhibitors, and efficacy of upstream Ras inhibition to alleviate the cardiac and extracardiac RIT1 phenotype.…”

Section: Discussionmentioning

confidence: 99%

Ras-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy

Cuevas-Navarro

Wagner

Van

et al. 2022

Preprint

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RIT1 belongs to the family of Ras guanosine triphosphatases (GTPases) that regulate many aspects of signal transduction and are drivers of cancer and congenital disorders. RIT1 gain-of-function mutations are found in lung cancer, leukemia, and in the germline of Noonan syndrome individuals with an increased prevalence of cardiac hypertrophy and other congenital heart defects. Pathogenic RIT1 proteins evade proteasomal degradation and promote MEK/ERK mitogen-activated protein kinase (MAPK) hyperactivation, yet the mechanism remains poorly understood. Here we show that RAF kinases are putative mutant RIT1 effectors necessary for MAPK activation and characterize RIT1 association with plasma membrane lipids and interaction with RAF kinases. We identify critical residues present in the RIT1 hypervariable region that facilitate interaction with negatively charged membrane lipids and show that these are necessary for association with RAF kinases. Although mutant RIT1 binds to RAF kinases directly, it fails to activate RAF-MAPK signaling in the absence of classical Ras proteins. Consistent with aberrant RAF/MEK/ERK activation as a driver of disease, we show that MEK inhibition alleviates cardiac hypertrophy in a mouse model of RIT1-mutant Noonan syndrome. These data shed light on pathogenic RIT1 function and identify avenues for therapeutic intervention.

show abstract

Succesful MEK-inhibition of severe hypertrophic cardiomyopathy in RIT1-related Noonan Syndrome

Cited by 13 publications

References 13 publications

Long-term outcomes of surgery for obstructive hypertrophic cardiomyopathy in a pediatric cohort

Long-term outcomes of surgery for obstructive hypertrophic cardiomyopathy in a pediatric cohort

RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome–associated cardiac hypertrophy

Ras-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy

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