{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:56:24Z","timestamp":1782280584717,"version":"3.54.5"},"posted":{"date-parts":[[2025,9,21]]},"group-title":"Cancer Biology","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,21]],"date-time":"2025-09-21T00:00:00Z","timestamp":1758412800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"National Cancer Institute of the National Institutes of Health","award":["P30 CA008748"],"award-info":[{"award-number":["P30 CA008748"]}]},{"name":"National Cancer Institute of the National Institutes of Health","award":["5P01CA129243-13"],"award-info":[{"award-number":["5P01CA129243-13"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,12]]},"abstract":"ABSTRACT<\/jats:title>\n \n Introduction<\/jats:title>\n \n RRAS<\/jats:italic>\n and\n RRAS2<\/jats:italic>\n encode a subfamily of RAS-like small GTPases that share considerable structural and functional similarities with\n KRAS<\/jats:italic>\n ,\n HRAS<\/jats:italic>\n , and\n NRAS.<\/jats:italic>\n Whether homologous\n RRAS<\/jats:italic>\n \/\n RRAS2<\/jats:italic>\n mutations are oncogenic and actionable drivers in lung cancer remains underexplored.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n An institutional cohort of 8,488 non-small cell lung carcinomas (NSCLC) sequenced by comprehensive targeted DNA sequencing (MSK-IMPACT) between 2016-2024 was evaluated for\n RRAS<\/jats:italic>\n \/\n RRAS2<\/jats:italic>\n mutations.\n RRAS<\/jats:italic>\n Q87L<\/jats:sup>\n or\n RRAS2<\/jats:italic>\n Q72L<\/jats:sup>\n were modeled in murine IL3-dependent Ba\/F3 cells and immortalized human bronchiolar epithelial cells (HBECs). The oncogenic potential, signaling characteristics, and sensitivity to PI3K and MAPK pathway inhibitors, including the novel pan-RAS inhibitor RMC-6236, were evaluated\n in vitro<\/jats:italic>\n and\n in vivo<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n RRAS<\/jats:italic>\n Q87L<\/jats:sup>\n or\n RRAS2<\/jats:italic>\n Q72L<\/jats:sup>\n , homologous to KRAS-codon Q61 substitutions, were found in \u223c0.45% of NSCLCs (38\/8,488), with all but two lacking other MAPK pathway oncogenic drivers. RRAS\n Q87L<\/jats:sup>\n and RRAS2\n Q72L<\/jats:sup>\n mutations transformed Ba\/F3 and HBEC cells and robustly activated MAPK and PI3K-mTOR pathway signaling. RMC-6236 suppressed proliferation of RRAS\n Q87L<\/jats:sup>\n and RRAS2\n Q72L<\/jats:sup>\n mutant cell lines, reduced ERK phosphorylation, induced apoptosis, and impeded cell-cycle progression.\n In vivo<\/jats:italic>\n , RMC-6236 significantly inhibited growth of\n RRAS<\/jats:italic>\n Q87L<\/jats:sup>\n \/\n RRAS2<\/jats:italic>\n Q72L<\/jats:sup>\n -mutant HBEC-derived xenografts.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n RRAS\n Q87L<\/jats:sup>\n and RRAS2\n Q72L<\/jats:sup>\n are recurrent, oncogenic, and potentially actionable drivers in NSCLC. Our study supports the inclusion of\n RRAS\/RRAS2<\/jats:italic>\n into routine molecular diagnostic panels for precision oncology and provides preclinical rationale for investigating the potential therapeutic utility of pan-RAS inhibitors for patients with RRAS\n Q87L<\/jats:sup>\n \/RRAS2\n Q72L<\/jats:sup>\n -mutant lung cancers.\n <\/jats:p>\n <\/jats:sec>\n \n Statement of translational relevance<\/jats:title>\n \n Targeted therapies have transformed standard of care for oncogene-driven non-small cell lung carcinomas (NSCLC), yet a significant subset lacks actionable drivers. We identified recurrent\n RRAS<\/jats:italic>\n Q87L<\/jats:sup>\n and\n RRAS2<\/jats:italic>\n Q72L<\/jats:sup>\n mutations which are mutually exclusive with other MAPK pathway drivers and found in \u223c0.45% of NSCLC, comparable in prevalence to\n NTRK<\/jats:italic>\n and\n NRG1<\/jats:italic>\n fusions. In preclinical models, these mutations activate canonical growth signaling, drive tumorigenic phenotypes, and confer sensitivity to RAS\/MAPK-directed agents, including the novel pan-RAS inhibitor RMC-6236, currently in trials for patients with solid tumors harboring\n KRAS<\/jats:italic>\n mutations. These data support\n RRAS<\/jats:italic>\n Q87L<\/jats:sup>\n and\n RRAS2<\/jats:italic>\n Q72L<\/jats:sup>\n as\n bona fide<\/jats:italic>\n lung cancer drivers and nominate RRAS\/RRAS2-mutant tumors as candidates for pan-RAS-targeted therapeutics. Our findings provide a biologic rationale and preclinical evidence to inform molecular testing paradigms and to prioritize enrollment of patients with RRAS\/RRAS2-mutant NSCLC into future clinical trials of pan-RAS inhibitors.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1101\/2025.09.19.677259","type":"posted-content","created":{"date-parts":[[2025,9,21]],"date-time":"2025-09-21T15:20:16Z","timestamp":1758468016000},"source":"Crossref","is-referenced-by-count":0,"title":["RRAS<\/i>\n and\n RRAS2<\/i>\n mutations are recurrent oncogenic drivers in lung cancer and are sensitive to the pan-RAS inhibitor RMC-6236"],"prefix":"10.64898","author":[{"given":"Alexander J.","family":"Pfeil","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065"},{"name":"University of North Carolina School of Medicine, Chapel Hill, NC, 27599"},{"name":"Graduate Medical Education, Memorial Sloan Kettering Cancer Center, 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