{
  "abstract": "Direct inhibitors of KRASG12C are now used as standard-of-care therapy in KRASG12C-mutant non–small cell lung cancer (NSCLC), but less is understood about the molecular mechanisms and consequent treatment vulnerabilities of KRAS codon 13 mutations in this setting. In this study, we characterized the tumorigenic properties of NSCLC harboring KRASG13X in a large multinational cohort of patients with NSCLC and in preclinical models of KRASG13X NSCLC. Induction of KRASG13C or KRASG13D expression confers reduced oncopotency compared with allele-specific controls affecting KRAS codon 12, particularly KRASG13C. We identified functionally relevant comutations in KRASG13X NSCLC, including KEAP1, STK11, BRAF, and NF1. The novel RAS(ON) G13C-selective inhibitor, RMC-8839, reduces viability in a panel of KRASG13C NSCLC cell models. To determine combination partners that enhance RAS(ON) mutant-selective inhibition, a drug repurposing screen revealed that KRASG13C models are selectively vulnerable to chemotherapy. Combination of docetaxel with RMC-8839 demonstrated robust antiproliferative activity in KRASG13C-driven NSCLC models in vitro and in vivo.\n\nSignificance:: We characterize the second most common KRAS mutational hotspot in NSCLC after codon 12, KRASG13X, from tumor initiation to advanced disease. KRASG13C is a novel, directly targetable subset of NSCLC, with vulnerability to the combination of chemotherapeutics and the mutant-selective RAS(ON) inhibitor RMC-8839, a finding immediately relevant to patient care.\n\nSee related commentary by Araujo and Skoulidi, p. 2206\n\nSee related article by Seamon et al., p. 2256",
  "abstract_shown": true,
  "affiliations": [
    "Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, United Kingdom.",
    "Cell Signaling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom.",
    "The Christie NHS Foundation Trust, Manchester, United Kingdom.",
    "Revolution Medicines, Redwood City, California.",
    "Department of Biochemistry and Molecular Biology, Faculty of Chemical Sciences, Complutense University of Madrid, Madrid, Spain.",
    "Cancer Research UK Lung Centre of Excellence, Manchester, United Kingdom.",
    "Department of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France.",
    "Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.",
    "Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), ICO-HUB Comprehensive Cancer Center, L’Hospitalet de Llobregat, Spain.",
    "Clinical Discovery Bioinformatics, Université Paris-Saclay, Institut Gustave Roussy, IHU PRISM, Villejuif, France.",
    "Inflammation and Cancer Plasticity Laboratory, Université Paris-Saclay, Inserm U981, Institut Gustave Roussy, IHU PRISM, Villejuif, France.",
    "Institut Gustave Roussy, Inserm, Prédicteurs Moléculaires et Nouvelles Cibles en Oncologie (U981), Université Paris-Saclay, Villejuif, France.",
    "Department of Pneumology, Thoracic Oncology Unit, AP-HP, Groupe Hospitalier HUPC, Hôpital Cochin, Paris, France.",
    "Centre de Recherche des Cordeliers, UMRS 1138 Complement, Inflammation and Cancer, Université Paris Descartes, Paris, France."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 33,
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        0,
        1
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      "name": "William J. McDaid",
      "orcid": "0009-0007-3442-4820"
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      "name": "Helen Adderley",
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      "name": "Paolo D. d’Arienzo",
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      "name": "Laura C. Woodhouse",
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      ],
      "name": "Yongxian Zhuang",
      "orcid": "0000-0001-8219-7764"
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      ],
      "name": "Sonia Castillo-Lluva",
      "orcid": "0000-0001-5357-7178"
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      ],
      "name": "Kirsten L. Tinsley",
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      "name": "James Cooksedge",
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      ],
      "name": "Martin J. Baker",
      "orcid": "0000-0002-9743-6294"
    },
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      ],
      "name": "Joshua Searle",
      "orcid": "0000-0002-1055-0247"
    },
    {
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        2,
        5
      ],
      "name": "Katherine D. Brown",
      "orcid": "0009-0007-5006-8379"
    },
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        2,
        5
      ],
      "name": "Mathew Carter",
      "orcid": "0009-0000-6732-1333"
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      ],
      "name": "Mihaela Aldea",
      "orcid": "0000-0001-7685-051X"
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      ],
      "name": "Arianna Marinello",
      "orcid": "0000-0003-3966-1984"
    },
    {
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        7
      ],
      "name": "Jacqueline V. Aredo",
      "orcid": "0000-0003-0559-3565"
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    {
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        8
      ],
      "name": "Nadia Gomez Serra",
      "orcid": "0009-0005-6708-3378"
    },
    {
      "affs": [
        8
      ],
      "name": "Maria Bisbe",
      "orcid": "0009-0007-2922-5368"
    },
    {
      "affs": [
        9
      ],
      "name": "Philip East",
      "orcid": "0000-0001-5801-5713"
    },
    {
      "affs": [
        10
      ],
      "name": "Sophie de Carné Trécesson",
      "orcid": "0000-0002-9341-2586"
    },
    {
      "affs": [
        11
      ],
      "name": "Fabrice Barlesi",
      "orcid": "0000-0001-5793-3539"
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    {
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        12,
        13
      ],
      "name": "Marie Wislez",
      "orcid": "0000-0001-7518-7859"
    },
    {
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        6
      ],
      "name": "Benjamin Besse",
      "orcid": "0000-0001-5090-8189"
    },
    {
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        7
      ],
      "name": "Heather A. Wakelee",
      "orcid": "0000-0003-1136-980X"
    },
    {
      "affs": [
        8
      ],
      "name": "Ernest Nadal",
      "orcid": "0000-0002-9674-5554"
    },
    {
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        2,
        5
      ],
      "name": "Fiona Blackhall",
      "orcid": "0000-0001-8716-3395"
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    {
      "affs": [
        0
      ],
      "name": "David C. Wedge",
      "orcid": "0000-0002-7572-3196"
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    {
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        3
      ],
      "name": "Matthew Holderfield",
      "orcid": "0000-0001-8474-3220"
    },
    {
      "affs": [
        3
      ],
      "name": "Jacqueline A.M. Smith",
      "orcid": "0000-0001-5028-8725"
    },
    {
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        3
      ],
      "name": "Mallika Singh",
      "orcid": "0009-0003-0234-1589"
    },
    {
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        3
      ],
      "name": "Kyle J. Seamon",
      "orcid": "0009-0005-5028-3752"
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    {
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        0,
        1,
        5
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      "name": "Angeliki Malliri",
      "orcid": "0000-0001-6848-090X"
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    {
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        0,
        2,
        5
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      "name": "Colin R. Lindsay",
      "orcid": "0000-0001-8167-5461"
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  "bibtex": "https://research.draconitic.com/paper/acc1fzk1s3y91.bib",
  "cited_by": 3,
  "doi": "10.1158/2159-8290.cd-25-0884",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13725345/",
  "id": "acc1fzk1s3y91",
  "issns": [
    "2159-8274",
    "2159-8290"
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  "landing_url": "https://doi.org/10.1158/2159-8290.cd-25-0884",
  "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",
      "Preclinical Models"
    ],
    [
      "heading",
      "Research Articles"
    ],
    [
      "heading",
      "Xenograft Models"
    ],
    [
      "openalex",
      "2740|Lung Cancer Treatments and Mutations"
    ]
  ],
  "openalex": "W7165528984",
  "pdf_url": null,
  "pmcid": "PMC13725345",
  "pmid": "42329102",
  "published": "2026-06-22",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/acc1fzk1s3y91.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T12:23:45Z",
      "native_id": "PMC13725345",
      "source": "pmc",
      "url": "https://doi.org/10.1158/2159-8290.cd-25-0884"
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2740|Lung Cancer Treatments and Mutations",
      "subfield": "general"
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  ],
  "title": "Targeting KRAS Codon 13 Mutations Using Direct Combination Approaches in Non–Small Cell Lung Cancer",
  "title_text": "Targeting KRAS Codon 13 Mutations Using Direct Combination Approaches in Non–Small Cell Lung Cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:21:38Z",
  "url": "https://research.draconitic.com/paper/acc1fzk1s3y91",
  "venue": "Cancer Discovery",
  "versions": []
}