{
  "abstract": "Aim: Cancer drug resistance is driven by dynamic, systems-level adaptations, including cellular state transitions, epigenetic reprogramming, metabolic rewiring, and proteome remodelling. Lipid metabolic reprogramming is increasingly recognised as a contributor to resistance through alterations in the membrane composition and has been hypothesised to promote resistance by increasing membrane rigidity and limiting drug permeability. Here we tested this hypothesis in melanoma using a cell state-resolved multi-omics approach. Methods: We combined lipidomics, surface-resolved phospholipid profiling, live-cell biophysical measurements, and whole-cell proteomics to characterise plasma membrane composition and function across drug-naïve, drug-tolerant persister, and permanently drug-resistant states in BRAFV600E metastatic melanoma cells treated with dabrafenib. Results: Lipidomic analyses revealed membrane remodelling, particularly in the drug-tolerant state, including altered fatty acid chain unsaturation, and increased cholesterol (Chol) and sphingomyelin levels. All cell states retained surface exposure of negatively charged phosphatidylserine and phosphatidylinositol. Despite compositional changes typically associated with membrane rigidification, plasma membrane fluidity and tension remain conserved across all resistance states. Proteomic analysis further revealed coordinated regulation of lipid metabolic pathways, including Chol homeostasis and sphingolipid turnover, indicating that lipid-metabolic adaptation supports survival under drug pressure without substantially altering membrane biophysical properties. Conclusion: These findings show that lipid metabolic rewiring supports drug tolerance while conserving core membrane features. By resolving resistance-associated changes across both molecular and biophysical layers, this study identifies shared plasma membrane features and vulnerabilities across heterogeneous melanoma cell populations, supporting the application of membrane-active therapeutic agents and of combination strategies targeting lipid-metabolic adaptations to delay or prevent resistance.",
  "abstract_shown": true,
  "affiliations": [
    "School of Biomedical Sciences, Centre for Microbiome Research and Centre for Immunology and Infectious Control, Faculty of Health, Queensland University of Technology, Translational Research Institute, Brisbane 4102, Australia.",
    "Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Queensland University of Technology, Brisbane 4102, Australia.",
    "Central Analytical Research Facility, Queensland University of Technology, Brisbane 4000, Australia.",
    "Molecular Horizons and School of Science, University of Wollongong, Wollongong 2500, Australia.",
    "Department of Chemistry, Graduate School of Science, University of Tokyo, Bunkyo-ku 113-0033, Japan.",
    "Institute for Molecular Bioscience, The University of Queensland, Brisbane 4072, Australia.",
    "Frazer Institute, The University of Queensland, Translational Research Institute, Brisbane 4102, Australia.",
    "Institute of Pharmaceutical Sciences/Pharmacognosy, University of Graz, Graz 8010, Austria.",
    "School of Chemistry and Physics, Faculty of Science, Queensland University of Technology, Brisbane 4000, Australia."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Aurélie H Benfield"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Reuben S E Young"
    },
    {
      "affs": [
        0,
        1,
        4
      ],
      "name": "Grégoire J B Philippe"
    },
    {
      "affs": [
        5
      ],
      "name": "Nicholas D Condon",
      "orcid": "0000-0002-1833-1129"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Nicolau Barbosa Palma Filho"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Helmut Schaider"
    },
    {
      "affs": [
        2,
        8
      ],
      "name": "Stephen J Blanksby"
    },
    {
      "affs": [
        0,
        1,
        5
      ],
      "name": "Sónia Troeira Henriques"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8q67yc503z3h3.bib",
  "cited_by": 0,
  "doi": "10.20517/cdr.2026.54",
  "fulltext_url": "https://europepmc.org/articles/PMC13680111",
  "id": "8q67yc503z3h3",
  "issns": [
    "2578-532X"
  ],
  "landing_url": "https://europepmc.org/article/MED/42903041",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Lipid Membrane Structure and Behavior"
    ]
  ],
  "openalex": "W7213274961",
  "pdf_url": "https://europepmc.org/articles/PMC13680111?pdf=render",
  "pmcid": "PMC13680111",
  "pmid": "42903041",
  "published": "2026-09-16",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/8q67yc503z3h3.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:57Z",
      "native_id": "MED:42903041",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42903041"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Lipid Membrane Structure and Behavior",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Adaptive drug resistance in melanoma is characterised by lipidome remodelling while maintaining cell membrane biophysical properties.",
  "title_text": "Adaptive drug resistance in melanoma is characterised by lipidome remodelling while maintaining cell membrane biophysical properties.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:57Z",
  "url": "https://research.draconitic.com/paper/8q67yc503z3h3",
  "venue": "Cancer drug resistance (Alhambra, Calif.)",
  "versions": []
}