{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T04:04:44Z","timestamp":1751515484341,"version":"3.41.0"},"reference-count":28,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:p>RASopathies are rare genetic disorders caused by germline mutations in genes that regulate the RAS\u2013mitogen-activated protein kinase (MAPK) pathway, a critical pathway involved in various cellular processes. Disruption of this pathway leads to multisystemic manifestations, including cardiomyopathies, a cause of high morbi-mortality. In response to the urgent need to improve survival in patients with RASopathies, alternative therapies, such as MAPK inhibitors traditionally used in cancer treatment, have been explored. This article reviews the current evidence on the use of these medications in treating cardiomyopathies associated with RASopathies. The search was conducted in the PubMed, Scopus, and Embase databases identifying nine studies reporting a total of 14 cases (nine with Noonan syndrome and five with Costello syndrome) where patients were successfully treated with trametinib, a MEK inhibitor. This therapeutic alternative broadens the horizons of opportunity for patients who often face limited options for enhancing their quality of life. Therefore, it is important to prioritize ongoing research in this field, focusing not only on further investigation on trametinib, but also exploring other potential therapeutic approaches.<\/jats:p>","DOI":"10.1097\/fpc.0000000000000569","type":"journal-article","created":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T18:00:10Z","timestamp":1748973610000},"page":"173-182","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Targeting cardiomyopathies associated with RASopathies: the role of mitogen-activated protein kinase inhibitors and therapeutic challenges"],"prefix":"10.1097","volume":"35","author":[{"given":"Valentina","family":"Botia-Arciniegas","sequence":"first","affiliation":[{"name":"Department of Basic Sciences, Faculty of Health Sciences"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Jimenez-Cardozo","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Faculty of Health Sciences"},{"name":"Grupo de Investigaci\u00f3n en Ciencias B\u00e1sicas y Cl\u00ednicas de la Salud, Pontificia Universidad Javeriana Cali, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juliana","family":"Lores","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Faculty of Health Sciences"},{"name":"Grupo de Investigaci\u00f3n en Ciencias B\u00e1sicas y Cl\u00ednicas de la Salud, Pontificia Universidad Javeriana Cali, Colombia"},{"name":"Clinical Genetics and Genomic Medicine Unit, Cl\u00ednica Imbanaco, Cali, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2025,6,4]]},"reference":[{"key":"R1-20250702","doi-asserted-by":"crossref","first-page":"dmm049107","DOI":"10.1242\/dmm.049107","article-title":"The RASopathies: from pathogenetics to therapeutics.","volume":"15","author":"Hebron","year":"2022","journal-title":"Dis Model Mech"},{"key":"R2-20250702","doi-asserted-by":"crossref","first-page":"1176828","DOI":"10.3389\/fcvm.2023.1176828","article-title":"RASopathies and cardiac manifestations.","volume":"10","author":"Hilal","year":"2023","journal-title":"Front Cardiovasc Med"},{"key":"R3-20250702","doi-asserted-by":"crossref","first-page":"e1239","DOI":"10.1161\/CIR.0000000000001250","article-title":"2024 AHA\/ACC\/AMSSM\/HRS\/PACES\/SCMR guideline for the management of hypertrophic cardiomyopathy: a report of the American Heart Association\/American College of Cardiology Joint Committee on Clinical Practice Guidelines.","volume":"149","author":"Ommen","year":"2024","journal-title":"Circulation"},{"key":"R4-20250702","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.bbadis.2009.12.009","article-title":"Pathological roles of MAPK signaling pathways in human diseases.","volume":"1802","author":"Kim","year":"2010","journal-title":"Biochim Biophys Acta"},{"key":"R5-20250702","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/nri3495","article-title":"Mitogen-activated protein kinases in innate immunity.","volume":"13","author":"Arthur","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"R6-20250702","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s00432-023-05572-7","article-title":"Natural products targeting the MAPK-signaling pathway in cancer: overview.","volume":"150","author":"Shi","year":"2024","journal-title":"J Cancer Res Clin Oncol"},{"key":"R7-20250702","first-page":"2365","article-title":"Constitutively active MAP kinase kinase (MEK1) stimulates SAP kinase and c-Jun transcriptional activity in U937 human leukemic cells.","volume":"11","author":"Franklin","year":"1995","journal-title":"Oncogene"},{"key":"R8-20250702","doi-asserted-by":"crossref","first-page":"171ra17","DOI":"10.1126\/scitranslmed.3004828","article-title":"Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects.","volume":"5","author":"Allen","year":"2013","journal-title":"Sci Transl Med"},{"key":"R9-20250702","doi-asserted-by":"crossref","first-page":"102379","DOI":"10.1016\/j.jaccas.2024.102379","article-title":"Treatment of RAF1-related obstructive hypertrophic cardiomyopathy by MEK inhibition using trametinib.","volume":"29","author":"Kiamanesh","year":"2024","journal-title":"JACC Case Rep"},{"key":"R10-20250702","doi-asserted-by":"crossref","first-page":"6","DOI":"10.3390\/genes13010006","article-title":"MEK inhibition in a newborn with \u2013 associated Noonan syndrome ameliorates hypertrophic cardiomyopathy but is insufficient to revert pulmonary vascular disease.","volume":"13","author":"Mussa","year":"2021","journal-title":"Genes (Basel)"},{"key":"R11-20250702","doi-asserted-by":"crossref","first-page":"101704","DOI":"10.1016\/j.ppedcard.2024.101704","article-title":"MEK inhibition in Noonan syndrome patient with severe cardiovascular and lymphatic disease.","volume":"72","author":"Torok","year":"2024","journal-title":"Prog Pediatr Cardiol"},{"key":"R12-20250702","doi-asserted-by":"crossref","first-page":"104630","DOI":"10.1016\/j.ejmg.2022.104630","article-title":"Succesful MEK-inhibition of severe hypertrophic cardiomyopathy in RIT1-related Noonan syndrome.","volume":"65","author":"Leegaard","year":"2022","journal-title":"Eur J Med Genet"},{"key":"R13-20250702","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1016\/j.jacc.2019.01.066","article-title":"Hypertrophic cardiomyopathy in Noonan syndrome treated by MEK-inhibition.","volume":"73","author":"Andelfinger","year":"2019","journal-title":"J Am Coll Cardiol"},{"key":"R14-20250702","doi-asserted-by":"crossref","first-page":"e003327","DOI":"10.1161\/CIRCGEN.121.003327","article-title":"Molecular management of multifocal atrial tachycardia in Noonan\u2019s syndrome with MEK1\/2 inhibitor trametinib.","volume":"14","author":"Meisner","year":"2021","journal-title":"Circ Genom Precis Med"},{"key":"R15-20250702","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.jpeds.2022.05.030","article-title":"Trametinib for refractory chylous effusions and systemic complications in children with Noonan syndrome.","volume":"248","author":"Nakano","year":"2022","journal-title":"J Pediatr"},{"key":"R16-20250702","doi-asserted-by":"crossref","first-page":"ytad190","DOI":"10.1093\/ehjcr\/ytad190","article-title":"Successful treatment of refractory chylothorax with MEK inhibitor trametinib in a child with Noonan syndrome: case report.","volume":"7","author":"Hribernik","year":"2023","journal-title":"Eur Heart J Case Rep"},{"key":"R17-20250702","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1016\/j.jacc.2023.02.010","article-title":"MEK inhibition improves cardiomyopathy in Costello syndrome.","volume":"81","author":"Geddes","year":"2023","journal-title":"J Am Coll Cardiol"},{"key":"R18-20250702","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.3390\/ijms20092164","article-title":"ERK: a key player in the pathophysiology of cardiac hypertrophy.","volume":"20","author":"Gallo","year":"2019","journal-title":"Int J Mol Sci"},{"key":"R19-20250702","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s13045-020-00949-4","article-title":"The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy.","volume":"13","author":"Yuan","year":"2020","journal-title":"J Hematol Oncol"},{"key":"R20-20250702","doi-asserted-by":"crossref","first-page":"101907","DOI":"10.1016\/j.ctrv.2019.101907","article-title":"Trametinib in the treatment of multiple malignancies harboring MEK1 mutations.","volume":"81","author":"Lian","year":"2019","journal-title":"Cancer Treat Rev"},{"key":"R21-20250702","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1002\/ehf2.15173","article-title":"Trametinib alters contractility of paediatric Noonan syndrome-associated hypertrophic myocardial tissue slices.","volume":"12","author":"Hamers","year":"2024","journal-title":"ESC Heart Fail"},{"key":"R22-20250702","doi-asserted-by":"crossref","first-page":"e90220","DOI":"10.1172\/jci.insight.90220","article-title":"Low-dose dasatinib rescues cardiac function in Noonan syndrome.","volume":"1","author":"Yi","year":"2016","journal-title":"JCI Insight"},{"key":"R23-20250702","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1172\/JCI44929","article-title":"MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1(L613V) mutation.","volume":"121","author":"Wu","year":"2011","journal-title":"J Clin Invest"},{"key":"R24-20250702","doi-asserted-by":"crossref","first-page":"4353","DOI":"10.1172\/JCI43910","article-title":"Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome\u2013associated Sos1 mutation.","volume":"120","author":"Chen","year":"2010","journal-title":"J Clin Invest"},{"key":"R25-20250702","doi-asserted-by":"crossref","first-page":"14074","DOI":"10.1073\/pnas.0610906104","article-title":"Genetic inhibition of cardiac ERK1\/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo.","volume":"104","author":"Purcell","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"R26-20250702","doi-asserted-by":"crossref","first-page":"e154215","DOI":"10.1172\/jci.insight.154215","article-title":"Inhibition of mTOR or MAPK ameliorates vmhcl\/myh7 cardiomyopathy in zebrafish.","volume":"6","author":"Bu","year":"2021","journal-title":"JCI Insight"},{"key":"R27-20250702","first-page":"731","article-title":"Exploring new drug repurposing opportunities for MEK inhibitors in RASopathies: a comprehensive review of safety, efficacy, and future perspectives of trametinib and selumetinib.","volume":"14","author":"Gazzin","year":"2024","journal-title":"Life (Basel)"},{"key":"R28-20250702","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3390\/ph15020195","article-title":"Exploring the natural compounds in flavonoids for their potential inhibition of cancer therapeutic target MEK1 using computational methods.","volume":"15","author":"AlZahrani","year":"2022","journal-title":"Pharmaceuticals (Basel)"}],"container-title":["Pharmacogenetics and Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.lww.com\/10.1097\/FPC.0000000000000569","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T09:00:14Z","timestamp":1751446814000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1097\/FPC.0000000000000569"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,4]]},"references-count":28,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025]]}},"URL":"https:\/\/doi.org\/10.1097\/fpc.0000000000000569","relation":{},"ISSN":["1744-6872","1744-6880"],"issn-type":[{"type":"print","value":"1744-6872"},{"type":"electronic","value":"1744-6880"}],"subject":[],"published":{"date-parts":[[2025,6,4]]}}}