{
  "abstract": "Daraxonrasib is an orally bioavailable RAS(ON) multi-selective tri-complex inhibitor of the oncogenic mutant and wild-type variants of N, H and KRAS. 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 KRAS 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 KRAS 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 KRAS and MYC 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.",
  "abstract_shown": true,
  "affiliations": [
    "Revolution Medicines, Redwood City, CA, USA",
    "Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA",
    "Broad Institute of MIT and Harvard, Cambridge, MA, USA",
    "Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA",
    "Harvard Medical School, Boston, MA, USA",
    "The Christ Hospital Health Network, Parkview Physician Group - Parkview Cancer Institute, Cincinnati, OH, USA",
    "NEXT Oncology Virginia, Virginia Cancer Specialists Research Institute, Fairfax, VA, USA",
    "Memorial Sloan Kettering Cancer Center, David M. Rubenstein Center for Pancreatic Cancer Research, Weill Cornell Medical College, New York, NY, USA",
    "The University of Texas MD Anderson Cancer Center, Department of Investigational Cancer Therapeutics, Houston, TX, USA",
    "University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA",
    "Mary Crowley Cancer Research, Texas Oncology, Dallas, TX, USA",
    "Sarah Cannon Research Institute, Nashville, TN, USA",
    "NEXT Oncology, San Antonio, TX, USA",
    "NYU Langone Health, Perlmutter Cancer Center, New York, NY, USA",
    "Revolution Medicines, Redwood City, CA, USA. klin@revmed.com",
    "Broad Institute of MIT and Harvard, Cambridge, MA, USA. andrew_aguirre@dfci.harvard.edu",
    "Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. andrew_aguirre@dfci.harvard.edu",
    "Harvard Medical School, Boston, MA, USA. andrew_aguirre@dfci.harvard.edu",
    "Revolution Medicines, Redwood City, CA, USA. msingh@revmed.com"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 46,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Ida Aronchik",
      "orcid": "0009-0002-1590-8778"
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    {
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        0
      ],
      "name": "Sumit Kar",
      "orcid": "0000-0002-8213-8497"
    },
    {
      "affs": [
        0
      ],
      "name": "Yongxian Zhuang",
      "orcid": "0000-0001-8219-7764"
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    {
      "affs": [
        0
      ],
      "name": "Ethan Ahler",
      "orcid": "0009-0001-0113-1956"
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    {
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        0
      ],
      "name": "Lo Lai",
      "orcid": "0009-0004-4395-1364"
    },
    {
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        0
      ],
      "name": "Vidya Seshadri",
      "orcid": "0009-0005-4400-8500"
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    {
      "affs": [
        0
      ],
      "name": "Yu Chi Yang",
      "orcid": "0000-0001-8318-1174"
    },
    {
      "affs": [
        1
      ],
      "name": "Ashenafi Shiferaw Bulle",
      "orcid": "0000-0001-6173-0769"
    },
    {
      "affs": [
        0
      ],
      "name": "Marie Ménard"
    },
    {
      "affs": [
        0
      ],
      "name": "Biswadeep Nayak"
    },
    {
      "affs": [
        0
      ],
      "name": "Mark P. Labrecque",
      "orcid": "0000-0001-7887-7599"
    },
    {
      "affs": [
        2,
        3,
        4
      ],
      "name": "Julien Dilly",
      "orcid": "0000-0002-4006-5285"
    },
    {
      "affs": [
        3
      ],
      "name": "Eejung Kim",
      "orcid": "0000-0003-0381-0992"
    },
    {
      "affs": [
        0
      ],
      "name": "Lingyan Jiang",
      "orcid": "0009-0006-7523-6968"
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    {
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        0
      ],
      "name": "Jason K. Yano",
      "orcid": "0000-0002-9774-2611"
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    {
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      ],
      "name": "Urszula N. Wasko",
      "orcid": "0009-0006-3029-2202"
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      ],
      "name": "Ciara Helland",
      "orcid": "0009-0009-3408-4517"
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    {
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      ],
      "name": "Sean Bredeson",
      "orcid": "0009-0003-8881-303X"
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    {
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        0
      ],
      "name": "Brett Garrick",
      "orcid": "0009-0003-9687-5820"
    },
    {
      "affs": [
        0
      ],
      "name": "Yevgeniy Gindin",
      "orcid": "0000-0001-8694-6849"
    },
    {
      "affs": [
        0
      ],
      "name": "Brad Sickler",
      "orcid": "0000-0002-7712-6301"
    },
    {
      "affs": [
        0
      ],
      "name": "Xing Wei",
      "orcid": "0000-0002-4584-3891"
    },
    {
      "affs": [
        0
      ],
      "name": "Kyle J. Seamon",
      "orcid": "0009-0005-5028-3752"
    },
    {
      "affs": [
        0
      ],
      "name": "Jingjing Jiang",
      "orcid": "0009-0004-2766-025X"
    },
    {
      "affs": [
        1
      ],
      "name": "Kian‐Huat Lim",
      "orcid": "0000-0002-2766-200X"
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    {
      "affs": [
        0
      ],
      "name": "Matthew T. Holderfield",
      "orcid": "0000-0001-8474-3220"
    },
    {
      "affs": [
        0
      ],
      "name": "Elsa Quintana",
      "orcid": "0000-0002-4123-1695"
    },
    {
      "affs": [
        0
      ],
      "name": "Aparna Hegde",
      "orcid": "0000-0001-6616-4882"
    },
    {
      "affs": [
        0
      ],
      "name": "Zeena Salman",
      "orcid": "0009-0009-3887-1542"
    },
    {
      "affs": [
        5
      ],
      "name": "Alexander Starodub"
    },
    {
      "affs": [
        6
      ],
      "name": "Alexander I. Spira",
      "orcid": "0000-0003-1303-0447"
    },
    {
      "affs": [
        7
      ],
      "name": "Wungki Park",
      "orcid": "0000-0002-8006-3102"
    },
    {
      "affs": [
        8,
        9
      ],
      "name": "David S. Hong",
      "orcid": "0000-0001-8721-1609"
    },
    {
      "affs": [
        10
      ],
      "name": "Minal A. Barve",
      "orcid": "0009-0007-4259-7457"
    },
    {
      "affs": [
        11
      ],
      "name": "Meredith S. Pelster",
      "orcid": "0009-0005-2448-3478"
    },
    {
      "affs": [
        12
      ],
      "name": "David Sommerhalder",
      "orcid": "0000-0002-7033-9064"
    },
    {
      "affs": [
        13
      ],
      "name": "Salman Rafi Punekar",
      "orcid": "0000-0002-7613-6305"
    },
    {
      "affs": [
        9
      ],
      "name": "Ignacio Garrido‐Laguna",
      "orcid": "0000-0003-2273-9028"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Brian Matthew Wolpin",
      "orcid": "0000-0002-0455-1032"
    },
    {
      "affs": [
        13
      ],
      "name": "Anirban Maitra",
      "orcid": "0000-0001-7923-9978"
    },
    {
      "affs": [
        0
      ],
      "name": "William Clay Gustafson",
      "orcid": "0000-0002-1812-5675"
    },
    {
      "affs": [
        0
      ],
      "name": "Steve M. Kelsey"
    },
    {
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        0
      ],
      "name": "Jacqueline A.M. Smith",
      "orcid": "0000-0001-5028-8725"
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        14
      ],
      "name": "Kevin K. Lin",
      "orcid": "0000-0003-4305-8352"
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        15,
        16,
        17
      ],
      "name": "Andrew J. Aguirre",
      "orcid": "0000-0002-0701-6203"
    },
    {
      "affs": [
        18
      ],
      "name": "Mallika Singh",
      "orcid": "0009-0003-0234-1589"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/58enhcet1j5v0.bib",
  "cited_by": 20,
  "doi": "10.1038/s41591-026-04537-w",
  "fulltext_url": null,
  "id": "58enhcet1j5v0",
  "issns": [
    "1078-8956",
    "1546-170X",
    "1744-7933"
  ],
  "landing_url": "https://doi.org/10.1038/s41591-026-04537-w",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2730|Pancreatic and Hepatic Oncology Research"
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  "pdf_url": "https://www.nature.com/articles/s41591-026-04537-w.pdf",
  "pmcid": "PMC13472880",
  "pmid": "42581230",
  "published": "2026-08-01",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/58enhcet1j5v0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:56Z",
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      "url": "https://doi.org/10.1038/s41591-026-04537-w"
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Pancreatic and Hepatic Oncology Research",
      "subfield": "oncology"
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  ],
  "title": "Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer",
  "title_text": "Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T13:20:50Z",
  "url": "https://research.draconitic.com/paper/58enhcet1j5v0",
  "venue": "Nature Medicine",
  "versions": []
}