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The prototypic RASopathy is Noonan syndrome, which has phenotypic overlap with related disorders such as cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome with multiple lentigines, and others. In this state\u2010of\u2010the\u2010art review, we summarize current knowledge on unmet therapeutic needs in these diseases and novel treatment approaches informed by insights from RAS\/MAPK\u2010associated cancer therapies, in particular through inhibition of MEK1\/2 and mTOR in patients with severe disease manifestations. We explore the possibilities of integrating a larger arsenal of molecules currently under development into future care plans. Lastly, we describe both medical and ethical challenges and opportunities for future clinical trials in the field.<\/jats:p>","DOI":"10.1002\/ajmg.c.32024","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T06:39:46Z","timestamp":1671431986000},"page":"541-560","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["New prospectives on treatment opportunities in\n                    <scp>RASopathies<\/scp>"],"prefix":"10.1002","volume":"190","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8527-5027","authenticated-orcid":false,"given":"Bruce D.","family":"Gelb","sequence":"first","affiliation":[{"name":"Mindich Child Health and Development Institute and Departments of Pediatrics and Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marielle E.","family":"Yohe","sequence":"additional","affiliation":[{"name":"Laboratory of Cell and Developmental Signaling Center for Cancer Research, National Cancer Institute  Frederick Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cordula","family":"Wolf","sequence":"additional","affiliation":[{"name":"Department of Congenital Heart Defects and Pediatric Cardiology German Heart Center Munich, School of Medicine &amp; Health, Technical University of Munich  Munich Germany"},{"name":"DZHK (German Centre for Cardiovascular Research) Partner Site Munich Heart Alliance  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9047-0502","authenticated-orcid":false,"given":"Gregor","family":"Andelfinger","sequence":"additional","affiliation":[{"name":"CHU Sainte Justine, Department of Pediatrics Universit\u00e9 de Montr\u00e9al  Montr\u00e9al Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,12,19]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-1351"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2019.01.066"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21031069"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-020-09902-w"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdv072"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c01371"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13180"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hfc.2017.12.005"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-5032"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav1444"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2022-056336"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.semtcvs.2021.07.027"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.112820"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-0066"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-3214"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvsv.2022.03.017"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00162-z"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-11-0824-T"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature00766"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noac165"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2020-0167"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30142-6"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30180-8"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2017.399"},{"issue":"1","key":"e_1_2_10_26_1","first-page":"131","article-title":"Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro","volume":"61","author":"End D. 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