{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T18:10:47Z","timestamp":1788891047909,"version":"build-2803163510"},"reference-count":39,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"954","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["Intramural Funds"],"award-info":[{"award-number":["Intramural Funds"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NIH R01 CA255232"],"award-info":[{"award-number":["NIH R01 CA255232"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2026,9,8]]},"abstract":"<jats:p>\n                    Wild-type RAS family members determine the signaling and therapeutic response in cancers driven by mutant HRAS and KRAS because they activate alternate RAS effector pathways. Here, we found that the requirement for wild-type RAS to support mutant NRAS\u2013driven transformation correlated with codon-specific differences in GTP hydrolysis. NRAS with mutations at either Gly\n                    <jats:sup>12<\/jats:sup>\n                    (G12X) or Gly\n                    <jats:sup>13<\/jats:sup>\n                    (G13X), which retained the GDP-GTP cycling function, had modest autonomous transforming potential. In contrast, NRAS with GTP-locking mutations at Gln\n                    <jats:sup>61<\/jats:sup>\n                    (Q61X mutants) was uncoupled from receptor tyrosine kinase (RTK) input, rendering wild-type RAS an obligate partner for RTK-stimulated signaling and oncogenesis. In RASless cells expressing mutant NRAS, reintroduction of wild-type HRAS was sufficient to restore signaling and transformation. Global dependency mapping in human cancer cells revealed functional partitioning, wherein mutant NRAS promoted MAPK signaling and wild-type HRAS promoted PI3K-AKT survival signaling. Consequently, allele-specific or pan-RAS(ON) inhibitors synergized with inhibitors of proximal RTK signaling or of wild-type HRAS or KRAS to overcome this signaling plasticity. Pan-RAS(ON) and HRAS inhibition was synergistic for all NRAS mutants tested, with Q61X mutants showing greater sensitivity. These findings define the signaling partnership between mutant NRAS and wild-type HRAS as a targetable vulnerability and provide a biochemical blueprint for dual RAS inhibition in\n                    <jats:italic toggle=\"yes\">NRAS<\/jats:italic>\n                    -mutated malignancies.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.aej6209","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T17:58:25Z","timestamp":1788890305000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["HRAS promotes mutant NRAS\u2013driven transformation with codon and allele specificity"],"prefix":"10.1126","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8230-8963","authenticated-orcid":true,"given":"Hyun","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA."},{"name":"Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD 20817, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6686-5014","authenticated-orcid":true,"given":"Jacob M.","family":"Hughes","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA."},{"name":"Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD 20817, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3160-0938","authenticated-orcid":true,"given":"Joseph P.","family":"LaMorte","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA."},{"name":"Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bridget A.","family":"Finniff","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA."},{"name":"Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD 20817, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Picabo","family":"Binette","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6616-3282","authenticated-orcid":true,"given":"Sarasi K.","family":"Gunasekara","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2611-559X","authenticated-orcid":true,"given":"Ariana","family":"Covas","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA."},{"name":"Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD 20817, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6972-239X","authenticated-orcid":true,"given":"Vanessa E.","family":"Wall","sequence":"additional","affiliation":[{"name":"Protein Expression Laboratory, NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9987-1687","authenticated-orcid":true,"given":"Dominic","family":"Esposito","sequence":"additional","affiliation":[{"name":"Protein Expression Laboratory, NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2727-0230","authenticated-orcid":true,"given":"Matthew D.","family":"Wilkerson","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5356-9426","authenticated-orcid":true,"given":"Marielle E.","family":"Yohe","sequence":"additional","affiliation":[{"name":"Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, NIH, Frederick, MD 21701, USA."},{"name":"Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1634-4882","authenticated-orcid":true,"given":"Robert L.","family":"Kortum","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.06.009"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-007-7133-8"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2016.05.098"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.05.018"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-15-0203"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1218173110"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.5c02061"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4389"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-3682"},{"key":"e_1_3_2_11_2","first-page":"1","article-title":"Ras signaling and therapies","volume":"102","author":"Young A.","year":"2009","unstructured":"A. Young, J. Lyons, A. L. Miller, V. T. Phan, I. R. Alarc\u00f3n, F. McCormick, Ras signaling and therapies. Adv. Cancer Res. 102, 1\u201317 (2009).","journal-title":"Adv. Cancer Res."},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0907325106"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1890"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.24.17164"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.37.24052"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.43.28155"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.09.004"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.11.059"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20121578"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.adx5186"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.182873"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.abn2694"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-14-0729"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.07.026"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-30881-9"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0231"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2010.7"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-23-1138"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-25-0022"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-024-00763-x"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-08931-1"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2022403118"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26526-y"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.02903"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2004.10.112"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0614"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.58204"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.10.4407-4416.2004"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aar8371"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2005966"}],"container-title":["Science Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scisignal.aej6209","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T17:58:30Z","timestamp":1788890310000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scisignal.aej6209"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,8]]},"references-count":39,"journal-issue":{"issue":"954","published-print":{"date-parts":[[2026,9,8]]}},"alternative-id":["10.1126\/scisignal.aej6209"],"URL":"https:\/\/doi.org\/10.1126\/scisignal.aej6209","relation":{},"ISSN":["1945-0877","1937-9145"],"issn-type":[{"value":"1945-0877","type":"print"},{"value":"1937-9145","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,8]]},"assertion":[{"value":"2026-06-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaej6209"}}