{
  "abstract": "Covalent KRASG12C inhibitors have changed the treatment landscape for patients with non–small cell lung cancer and colorectal cancer, but numerous RAS-mutant cancers lack approved targeted therapies. In this study, we describe RMC-8839, an oral RAS(ON) G13C-selective, covalent, tricomplex inhibitor that induced tumor regressions in selected KRASG13C-mutant xenograft models. However, one third of KRASG13C-mutant human cancer cell lines in vitro showed incomplete RAS pathway suppression despite near-complete KRASG13C engagement, suggesting a role for wild-type RAS(ON). We find that codon 13–mutant RAS differs from other KRAS mutations, exhibiting decreased stability, increased nucleotide exchange, and substantial intrinsic and guanosine triphosphatase-activating protein–stimulated GTP hydrolysis, which decreases oncogenicity. Furthermore, co-occurring RAS pathway mutations leading to increased wild-type RAS activation are enriched in codon 13–mutant tumors. Consistent with a role for wild-type RAS(ON) signaling, the combination of RMC-8839 with a RAS(ON) multiselective inhibitor resulted in deeper inhibition of KRASG13C-mutant xenograft tumor growth than either inhibitor alone.\n\nSignificance:: An enhanced understanding of the underlying biology of RAS mutations is critical to inform therapeutic strategies. Our preclinical data highlight that codon 13 mutant tumors are more reliant on wild-type RAS signaling than codon 12 tumors and demonstrate that this can be addressed by combining RAS(ON) G13C-selective and multiselective inhibitors.\n\nSee related commentary by Araujo and Skoulidi, p. 2206\n\nSee related article by McDaid et al., p. 2274",
  "abstract_shown": true,
  "affiliations": [
    "Revolution Medicines, Inc., Redwood City, California."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 22,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Kyle J. Seamon",
      "orcid": "0009-0005-5028-3752"
    },
    {
      "affs": [
        0
      ],
      "name": "Yongxian Zhuang",
      "orcid": "0000-0001-8219-7764"
    },
    {
      "affs": [
        0
      ],
      "name": "Yu Chi Yang",
      "orcid": "0000-0001-8318-1174"
    },
    {
      "affs": [
        0
      ],
      "name": "Sujata Chakraborty",
      "orcid": "0000-0003-0080-3180"
    },
    {
      "affs": [
        0
      ],
      "name": "James Cregg",
      "orcid": "0000-0002-2871-0800"
    },
    {
      "affs": [
        0
      ],
      "name": "Aidan C.A. Tomlinson",
      "orcid": "0000-0002-9663-773X"
    },
    {
      "affs": [
        0
      ],
      "name": "Andrea Gould",
      "orcid": "0009-0003-5132-2544"
    },
    {
      "affs": [
        0
      ],
      "name": "Ethan Ahler",
      "orcid": "0009-0001-0113-1956"
    },
    {
      "affs": [
        0
      ],
      "name": "Benjamin J. Maldonato",
      "orcid": "0000-0001-6560-0224"
    },
    {
      "affs": [
        0
      ],
      "name": "Jessica N. Spradlin",
      "orcid": "0000-0001-7278-6645"
    },
    {
      "affs": [
        0
      ],
      "name": "Kristof Pota",
      "orcid": "0000-0002-9027-0201"
    },
    {
      "affs": [
        0
      ],
      "name": "Caroline Weller",
      "orcid": "0009-0000-0381-3822"
    },
    {
      "affs": [
        0
      ],
      "name": "Abby Marquez",
      "orcid": "0000-0001-5104-2823"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhican Wang",
      "orcid": "0000-0002-9411-9349"
    },
    {
      "affs": [
        0
      ],
      "name": "Elena S. Koltun",
      "orcid": "0009-0005-8720-9097"
    },
    {
      "affs": [
        0
      ],
      "name": "John E. Knox",
      "orcid": "0009-0006-6246-5198"
    },
    {
      "affs": [
        0
      ],
      "name": "Adrian L. Gill",
      "orcid": "0009-0003-0914-4860"
    },
    {
      "affs": [
        0
      ],
      "name": "Jacqueline A.M. Smith",
      "orcid": "0000-0001-5028-8725"
    },
    {
      "affs": [
        0
      ],
      "name": "Mallika Singh",
      "orcid": "0009-0003-0234-1589"
    },
    {
      "affs": [
        0
      ],
      "name": "Jingjing Jiang",
      "orcid": "0009-0004-2766-025X"
    },
    {
      "affs": [
        0
      ],
      "name": "David Wildes",
      "orcid": "0009-0009-3855-7270"
    },
    {
      "affs": [
        0
      ],
      "name": "Matthew Holderfield",
      "orcid": "0000-0001-8474-3220"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cht032kfghb9f.bib",
  "cited_by": 2,
  "doi": "10.1158/2159-8290.cd-25-0886",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13725342/",
  "id": "cht032kfghb9f",
  "issns": [
    "2159-8274",
    "2159-8290"
  ],
  "landing_url": "https://doi.org/10.1158/2159-8290.cd-25-0886",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Biochemistry"
    ],
    [
      "heading",
      "Drug Targets"
    ],
    [
      "heading",
      "Oncogenes & Tumor Suppressors"
    ],
    [
      "heading",
      "Pharmacology"
    ],
    [
      "heading",
      "Research Articles"
    ],
    [
      "openalex",
      "1312|Protein Kinase Regulation and GTPase Signaling"
    ]
  ],
  "openalex": "W7165573548",
  "pdf_url": null,
  "pmcid": "PMC13725342",
  "pmid": "42329095",
  "published": "2026-06-22",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/cht032kfghb9f.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T12:23:45Z",
      "native_id": "PMC13725342",
      "source": "pmc",
      "url": "https://doi.org/10.1158/2159-8290.cd-25-0886"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "heading:Biochemistry",
      "subfield": "general"
    },
    {
      "field": "medicine",
      "origin": "heading:Pharmacology",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Selective Inhibition of KRASG13C Reveals an Increased Dependence on Wild-type RAS Isoforms in Codon 13 RAS-Mutant Cancers",
  "title_text": "Selective Inhibition of KRASG13C Reveals an Increased Dependence on Wild-type RAS Isoforms in Codon 13 RAS-Mutant Cancers",
  "type": "peer-reviewed",
  "updated_at": "2026-11-04T12:23:45Z",
  "url": "https://research.draconitic.com/paper/cht032kfghb9f",
  "venue": "Cancer Discovery",
  "versions": []
}