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We previously reported encouraging efficacy in a phase 1\/2 clinical trial evaluating daraxonrasib monotherapy at clinically active dose levels in patients with previously treated, RAS mutant metastatic pancreatic adenocarcinoma (PDAC), providing the basis for confirmatory evaluation in the randomized phase 3 RASolute 302 clinical trial. Here we report mechanisms of acquired resistance to daraxonrasib monotherapy observed through targeted sequencing of over 800 genes in paired pretreatment and end of treatment circulating tumor DNA samples from 44 patients in the phase 1\/2 clinical trial. Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26 of 44; 59%) of these patients, including, most notably, mutant\n                    <jats:italic>KRAS<\/jats:italic>\n                    amplifications in one-third (16 of 44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4 of 44; 9%), MAPK (11 of 44; 25%) and PI3K (4 of 44; 9%) pathways. Notably, no acquired secondary\n                    <jats:italic>KRAS<\/jats:italic>\n                    mutations were observed, distinct from resistance profiles of mutant-selective KRAS G12C(OFF) inhibitors. To corroborate these clinical findings, we found, or mechanistically established, concordant mechanisms of daraxonrasib resistance in human and murine preclinical models of PDAC, including mutant\n                    <jats:italic>KRAS<\/jats:italic>\n                    and\n                    <jats:italic>MYC<\/jats:italic>\n                    amplification and RTK upregulation, with these alterations guiding various combination therapy concepts. Notably, daraxonrasib combined with agents targeting DNA damage response, RTKs or the mutant-selective RAS(ON) G12D inhibitor zoldonrasib averted resistance in preclinical models. Collectively, these results show that most daraxonrasib genomic resistance mechanisms drive reactivation of RAS pathway signaling and guide potential combination strategies in PDAC for further investigation.\n                  <\/jats:p>","DOI":"10.1038\/s41591-026-04537-w","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T09:03:49Z","timestamp":1786439029000},"page":"2865-2877","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic 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This has now been corrected so that Ida Aronchik and Sumit Kar are listed as equal contributors, and a sentence has been added to the Author contributions stating that Yongxian Zhuang, Ethan Ahler and Lick Pui Lai are co-second authors. This correction has been made to the HTML and PDF versions of the article.","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"I.A., S. Kar, Y.Z., E.A., L.P.L., V.S., Y.C.Y., M.M., B.N., M.P.L., L.J., J.Y., U.N.W., C.H., S.B., B.G., Y.G., B.S., X.W., K.S., J.J., M.H., E.Q., A.H., Z.S., W.C.G., S. Kelsey, J.A.M.S., K.K.L. and M.S. are current or former employees of Revolution Medicines and may hold stock, stock options and\/or other equity interests in the company. M.S. is an inventor on pending patent applications WO2022060836, WO2024229406, WO2025019318, WO2025217307 and WO2025160221 filed by Revolution Medicines. W.C.G. is an inventor on pending patent applications WO2025019318 and WO2026090245 filed by Revolution Medicines. Z.S. is an inventor on pending patent application WO2025019318 filed by Revolution Medicines. J.J. is an inventor on pending patent applications WO2025019318, WO2024229406, WO2025217307 and WO2025160221 filed by Revolution Medicines. I.A. is an inventor on pending patent applications WO2024229406 and WO2025217307 filed by Revolution Medicines. E.Q. is an inventor on pending patent applications WO2024229406, WO2025217307 and WO2026090245 filed by Revolution Medicines. Y.Z. is an inventor on pending patent application WO2024229406 filed by Revolution Medicines. L.J. is an inventor on pending patent application WO2024229406 filed by Revolution Medicines. X.W. is an inventor on pending patent application WO2024229406 filed by Revolution Medicines. K.S. is an inventor on pending patent application WO2024229406 filed by Revolution Medicines. M.P.L. is an inventor on pending patent application WO2024229406 filed by Revolution Medicines. M.M. is an inventor on pending patent applications WO2024229406 and WO2026090245 filed by Revolution Medicines. Y.C.Y. is an inventor on pending patent application WO2024229406 filed by Revolution Medicines. U.N.W. is an inventor on pending patent application WO2025160221 filed by Revolution Medicines. K.-H.L. serves as a site principal investigator for Revolution Medicines-sponsored clinical trials and participates in a speaker bureau related to daraxonrasib. K.-H.L. receives funding through the Washington University PDXNet PDX Development and Trial Center (NCI U54CA224083). A.J.A. has consulted for Affini-T Therapeutics, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Curie.Bio, Incyte, Ipsen, Kestrel Therapeutics, Merck & Co., Mirati Therapeutics, Nimbus Therapeutics, Oncorus, Persistence Therapeutics, Plexium, Quanta Therapeutics, Reactive Biosciences, Revolution Medicines, Riva Therapeutics, Servier Pharmaceuticals, Syros Pharmaceuticals, Taiho Pharmaceuticals, T-knife Therapeutics, Third Rock Ventures and Ventus Therapeutics; holds equity in Riva Therapeutics and Kestrel Therapeutics; and has received research funding from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Deerfield, Eli Lilly, Mirati Therapeutics, Novartis, Novo Ventures and Revolution Medicines. A.J.A. is supported by Break Through Cancer, the Lustgarten Foundation, the Pancreatic Cancer Action Network, the Mark Foundation, the DeGregorio Family Foundation, National Institutes of Health (NIH)\/National Cancer Institute (NCI) P50CA127003, U01CA274276, R01CA276268 and the Dana-Farber Cancer Institute Hale Center for Pancreatic Cancer Research. B.M.W. reports research support to Dana-Farber Cancer Institute from Agios, Amgen, AstraZeneca, Break Through Cancer, Eli Lilly, Harbinger Health, Lustgarten Foundation, the Mark Foundation for Cancer Research, NIH\/NCI, Novartis, the Pancreatic Cancer Action Network, Revolution Medicines, Stand Up To Cancer and Stephenson Pancreatic Cancer Research. B.M.W. has served on consulting or advisory boards for Agenus, BeiGene, Cancer Panels, EcoR1 Capital, GRAIL, Harbinger Health, Immuneering Corporation, Ipsen, Lustgarten Foundation, Mirati Therapeutics\/Bristol Myers Squibb, Revolution Medicines, SystImmune, Takeda, Tango Therapeutics, TD Cowen and Third Rock Ventures. A.M. is an employee of NYU Langone Health and is an inventor on intellectual property licensed by Johns Hopkins University to Exact Sciences (an Abbott Laboratories company). W.P. reports research funding to his institution from NIH\/NCI, Break Through Cancer, Parker Institute for Cancer Immunotherapy, the Society for Immunotherapy of Cancer, the Society of MSK, Merck, Astellas, Revolution Medicines, Lepu Biopharma, Amgen, Fortvita and Verastem Oncology. He has served as a consultant or advisory board member for Astellas, Revolution Medicines, Innovent Biologics, Regeneron, KeyQuest, IMGT, Expert Connect and TD Cowen. He has received honoraria for Continuing Medical Education activities from American Physician Institute, Curio, Integrity, EPICS, SignifyMD and PER, and travel support from Amgen and DAVA Oncology. He has licensing interests related to Saccharo and is an inventor on an unlicensed provisional US patent application related to Microhomology-mediated End-joining Deletion Footprints as a genomic biomarker reflecting POLQ-driven DNA repair-associated immunogenicity in homologous recombination-deficient tumors. D.S.H. reports institutional research funding from AbbVie, Acendo, Adagene, Adaptimmune, Adlai-Nortye, Alterome, Amgen, Arvinas, AstraZeneca, Bayer, BeiGene, BridgeBio, Bristol Myers Squibb, Chong Kun, D3 Bio, Deciphera, Eli Lilly, Endeavor, Erasca, Exelixis, Genentech\/Roche, Immunogenesis, Inhibrix, Kestrel Therapeutics, Kumquat, Kura Oncology, NCI-CTEP, Pfizer, Quanta Therapeutics, Revolution Medicines, VelaVigo, Verastem and VM Oncology. D.S.H. reports consulting, advisory or speaker activities with AbbVie, Acuta, Alpha Insights, Amgen, Axiom, Blueprint Medicines, BeiGene, Boxer Capital, BVF Consulting, ClearView Oncology, COR2ed, Cogent Therapeutics, CureBio, EcoR1, Erasca, GLG, Guidepoint, HuyaBio, Immunogenesis, Kanaph Therapeutics, Kayak Therapeutics, Kestrel Therapeutics, Medscape, Morgan Stanley, Nextech Ventures, Pfizer, PharmaResearch, Revolution Medicines, T-Knife Therapeutics and WebMD. D.S.H. reports ownership or advisory interests in BreakThrough Bio, CrossBridge Bio, Molecular Match, OncoResponse, Telperian and Interact Therapeutics. M.P. reports research funding to her institution from multiple commercial sponsors, including AbbVie, Affini-T Therapeutics, Arcus Biosciences, Astellas, AstraZeneca, BeiGene, BioNTech, Boehringer Ingelheim, CytomX, Daiichi Sankyo, Frontier Medicines, GSK, HiberCell, Ipsen, Janssen, Jazz Pharmaceuticals, Kura Oncology, Quanta Therapeutics, Revolution Medicines, Roche, Seagen, Takeda and others. M.P. reports consulting or advisory roles with BeOne Medicines, Bicycle Therapeutics, Bristol Myers Squibb, Curio Science, CytomX, Genentech\/Roche, Kura Oncology, Novocure, Onviv, Pfizer, Revolution Medicines and Takeda. S.R.P. has received consulting fees from Regeneron, Cogent Biosciences and Revolution Medicines and travel support from Revolution Medicines and A2 Biotherapeutics and serves on the clinical advisory boards of Moonlight Bio and A2 Biotherapeutics. I.G.-L. reports consulting or advisory roles with AbbVie, EcoR1 Capital, Eli Lilly, Guidepoint, Innovent, Jazz Pharmaceuticals, Kanaph Therapeutics, Kestrel Therapeutics, KeyQuest Health, OncXerna, Quanta Therapeutics, Revolution Medicines and SOTIO. A. Spira serves in a leadership role with NEXT Oncology Virginia. He has received honoraria from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, CytomX Therapeutics, Eli Lilly, Janssen Oncology, Merck, Novartis, Prelude Therapeutics and Takeda. He has served as a consultant or advisor to Amgen, ArriVent Biopharma, AstraZeneca, Black Diamond Therapeutics, CRISPR Therapeutics, Daiichi Sankyo, GSK, Gritstone Oncology, Incyte, Janssen Research & Development, Jazz Pharmaceuticals, Lilly, Mersana, Mirati Therapeutics, Novartis, Regeneron, Revolution Medicines, Sanofi, Synthekine and Takeda. He has received institutional research funding from multiple commercial sponsors, including AbbVie, Amgen, ArriVent Biopharma, AstraZeneca, Astellas, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Incyte, Lepu Biopharma, Novartis, Regeneron, Revolution Medicines, Roche, Scorpion Therapeutics, Takeda and Tango Therapeutics. D.S. is an employee and shareholder of Texas Oncology and holds stock in IQVIA. He has received honoraria from Syneos, consulting fees from Guidepoint, and advisory board compensation from AbbVie, Cartography Biosciences, Revolution Medicines and Nimbus Therapeutics. D.S. reports institutional research funding for clinical studies from AbbVie, Acrivon Therapeutics, ADC Therapeutics, Alentis Therapeutics, Aprea Therapeutics, Ascentage Pharma Group, Astellas, AstraZeneca, Avenzo Therapeutics, Axion Bio, Biomea Fusion, Boehringer Ingelheim, BJ Bioscience, BioNTech, Bristol Myers Squibb, Cartography Biosciences, Compugen, CSPC Megalith Biopharmaceutical, D3 Bio, Day One Biopharma, Dewpoint Therapeutics, Dicerna\/Novo Nordisk, Dren Bio, DualityBio, Erasca, Exelixis, Fate Therapeutics, Gilead Sciences, GSK, Haihe Pharmaceutical, Iconovir Bio, IDEAYA Biosciences, Immuneering, Impact Therapeutics, Incendia, Ipsen, Kura Oncology, MediLink Therapeutics, Mirati Therapeutics, ModeX Therapeutics, Monopteros Therapeutics, Navire Pharma, Nimbus Therapeutics, NGM Biopharmaceuticals, Normunity, OBI Pharma, OncoResponse, Pfizer, PMV Pharma, ProteinQure, Revolution Medicines, Shanghai Hansoh Biomedical, Step Pharmaceuticals, Sutro Biopharma, Symphogen, SystImmune, Tachyon Therapeutics, Teon Therapeutics, Tyligand Bioscience, VelaVigo Pharma, Vincerx Pharma, Vividion Therapeutics, Ziel Bio and Zymeworks. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}