{
  "abstract": "Epidermal growth factor receptor (EGFR) mutations drive up to 50% of non-small-cell lung cancers (NSCLC). Although tyrosine kinase inhibitors (TKIs) like gefitinib initially offer substantial clinical benefit, the emergence of acquired, on-target resistance inevitably limits long-term remission. Beyond structural changes that alter ATP-pocket affinity, EGFR oligomerization drives this resistance, though the underlying mechanisms remain unclear. Here we show that progressive, TKI-resistant secondary and tertiary EGFR-mutant variants assemble on the cell surface into higher-order, ligand-free oligomers organized around pathological catalytic trimers. In contrast, gefitinib-sensitive variants assemble into oligomers where the catalytic units remain as canonical dimers, like those found in wild-type oligomers. Genetically disrupting these pathological trimers into dimers via a single-point mutation rewires downstream signaling, decelerates tumor progression, and reverses gefitinib resistance in vivo. Conversely, genetic engineering of dimers into trimers reinstates aggressive tumor growth. These findings expose a structural vulnerability unique to acquired mutations, demonstrating that selectively targeting these pathological intra-oligomer trimers can overcome resistance, and provide a blueprint for protein-protein interface modulation strategies that spare wild-type signaling.",
  "abstract_shown": true,
  "affiliations": [
    "Central Laser Facility, UKRI-STFC Rutherford Appleton Laboratory, Didcot, Oxfordshire, UK"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "name": "S. K. Roberts"
    },
    {
      "name": "I. Galdadas"
    },
    {
      "name": "N. Piasentin"
    },
    {
      "name": "S. R. Needham"
    },
    {
      "name": "L. C. Zanetti-Domingues"
    },
    {
      "name": "B. M. Davis"
    },
    {
      "name": "R. C. H. Man"
    },
    {
      "name": "D. T. Clarke"
    },
    {
      "name": "A. H. A. Clayton"
    },
    {
      "name": "D. J. Rolfe"
    },
    {
      "name": "G. O. Fruhwirth"
    },
    {
      "name": "F. L. Gervasio"
    },
    {
      "affs": [
        0
      ],
      "name": "M. L. Martin-Fernandez"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/f2bmd1bqgjr1a.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.24.754095",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.24.754095v1.full",
  "id": "f2bmd1bqgjr1a",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.24.754095v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "openalex",
      "2740|Lung Cancer Treatments and Mutations"
    ]
  ],
  "openalex": "W7214309762",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.24.754095v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-24",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/f2bmd1bqgjr1a.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:24:31Z",
      "native_id": "10.64898/2026.09.24.754095",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.24.754095v3"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Disrupting aberrant EGFR catalytic trimers reverses T790M gefitinib resistance",
  "title_text": "Disrupting aberrant EGFR catalytic trimers reverses T790M gefitinib resistance",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:28Z",
  "url": "https://research.draconitic.com/paper/f2bmd1bqgjr1a",
  "venue": "bioRxiv",
  "versions": []
}