{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T07:26:23Z","timestamp":1786778783458,"version":"build-2736575974"},"reference-count":51,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    RAS mutations occur in patients with several types of vascular anomalies, but effective treatments remain limited. To address this need, we evaluated the RAS (ON) multi\u2010selective inhibitor RMC\u20107977 in human endothelial cells (ECs) expressing the NRAS\n                    <jats:sup>Q61R<\/jats:sup>\n                    mutation found in kaposiform lymphangiomatosis (KLA). RMC\u20107977 was evaluated using in\u00a0vitro and in\u00a0vivo models. Doxycycline\u2010inducible NRAS\n                    <jats:sup>WT<\/jats:sup>\n                    and NRAS\n                    <jats:sup>Q61R<\/jats:sup>\n                    human ECs were treated with RMC\u20107977 (3.12\u2013100\u2009nM) or vehicle. We assessed signalling pathways, proliferation, migration, morphology, and angiopoietin\u20102 (ANG\u20102) production. NRAS\n                    <jats:sup>Q61R<\/jats:sup>\n                    ECs in a 3D angiogenesis assay were also treated with RMC\u20107977. For in\u00a0vivo studies, NRAS\n                    <jats:sup>Q61R<\/jats:sup>\n                    ECs were injected into flanks of nude mice on a doxycycline diet to generate xenografts. Mice received oral RMC\u20107977 or vehicle, and xenografts were collected after 11\u2009days. RMC\u20107977 inhibited NRAS\n                    <jats:sup>Q61R<\/jats:sup>\n                    \u2010induced ERK phosphorylation and reduced proliferation, migration, spindle\u2010like morphology, and ANG\u20102 production in a dose\u2010dependent manner. RMC\u20107977 reduced vascular area in the angiogenesis assay. In\u00a0vivo, RMC\u20107977 reduced xenograft weight, vascular area, and p\u2010ERK staining. Overall, RMC\u20107977 suppressed NRAS\n                    <jats:sup>Q61R<\/jats:sup>\n                    \u2010mediated signalling, aberrant EC behaviour, and ANG\u20102 production in\u00a0vitro and reduced vascular overgrowth in angiogenesis assays and mouse xenografts. Therefore, RMC\u20107977 may be a promising therapeutic candidate for RAS\u2010driven vascular anomalies, including KLA.\n                  <\/jats:p>","DOI":"10.1111\/jcmm.71316","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T06:51:13Z","timestamp":1786431073000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>RAS<\/scp>\n                    Inhibitor\n                    <scp>RMC<\/scp>\n                    \u20107977 Blocks Vascular Overgrowth of\n                    <i>\n                      NRAS\n                      <sup>Q61R<\/sup>\n                    <\/i>\n                    Mutant Endothelial Cells"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4477-9592","authenticated-orcid":false,"given":"Sara","family":"Alharbi","sequence":"first","affiliation":[{"name":"Department of Cancer Biology University of Cincinnati College of Medicine  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"},{"name":"Division of Pulmonary Biology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7604-3849","authenticated-orcid":false,"given":"Svatava","family":"Merkle","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"},{"name":"Division of Pulmonary Biology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Division of Hematology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Pastura","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Biology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0573-0956","authenticated-orcid":false,"given":"C. Griffin","family":"McDaniel","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"},{"name":"Division of Pulmonary Biology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3088-218X","authenticated-orcid":false,"given":"George S.","family":"Zaky","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"},{"name":"Division of Pulmonary Biology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6058-5878","authenticated-orcid":false,"given":"Andrew M.","family":"Waters","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology University of Cincinnati College of Medicine  Cincinnati Ohio USA"},{"name":"Department of Surgery University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8538-2703","authenticated-orcid":false,"given":"Timothy D.","family":"Le Cras","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"},{"name":"Division of Pulmonary Biology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/JOVA.0000000000000113"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.4329\/wjr.v6.i9.677"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232012199"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.31605"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2020.579591"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2023.1099328"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2960"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.4161\/sgtp.1.1.12178"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20220234"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.01088"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.06.009"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00671-9"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07379-z"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07205-6"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1917239"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2204619"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06123-3"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2208470"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2103695"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0027"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-018-0390-0"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02364-x"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1709449"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-022-09836-7"},{"issue":"8","key":"e_1_2_11_26_1","article-title":"Pathophysiology in Brain Arteriovenous Malformations: Focus on Endothelial Dysfunctions and Endothelial\u2010To\u2010Mesenchymal Transition","volume":"12","author":"Jeong J. Y.","year":"2024","journal-title":"Biomedicine"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.wneu.2019.03.105"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-024-09918-8"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-019-1191-5"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202012324"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-016-9537-2"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.27878"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1097\/JOVA.0000000000000124"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/1545-5017.70002"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.31032"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.28529"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/noajnl\/vdaf065"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.31984"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0614"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2024.104250"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdu482"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2015-3257"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.23124"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41390-022-01986-0"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.32119"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-024-03211-z"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2309160"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/1545-5017.70339"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2023.1276333"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.31492"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddae080"},{"key":"e_1_2_11_52_1","article-title":"A High\u2010Throughput Zebrafish Screen Identifies Novel Candidate Treatments for Kaposiform Lymphangiomatosis (KLA)","volume":"222","author":"Bassi I.","year":"2024","journal-title":"Journal of Experimental Medicine"}],"container-title":["Journal of Cellular and Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jcmm.71316","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jcmm.71316","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jcmm.71316","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T06:41:53Z","timestamp":1786776113000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jcmm.71316"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":51,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1111\/jcmm.71316"],"URL":"https:\/\/doi.org\/10.1111\/jcmm.71316","archive":["Portico"],"relation":{},"ISSN":["1582-1838","1582-4934"],"issn-type":[{"value":"1582-1838","type":"print"},{"value":"1582-4934","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8]]},"assertion":[{"value":"2026-04-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e71316"}}