{
  "abstract": "Background: HER2-directed CAR-T cells can eradicate melanoma despite low HER2 expression. We therefore asked whether melanoma would also respond to trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate targeting HER2. Patients and methods: T-DXd was evaluated in several patient-derived xenograft (PDX) models and as a compassionate use in one patient with metastatic uveal melanoma. We compared T-DXd with another ADC, trastuzumab emtansine (T-DM1), and examined ADC sensitivity and trastuzumab uptake in vitro, and expression of HER2 and cathepsin L (CTSL) in xenografts. Results: T-DXd inhibited all subcutaneous PDXs, while liver models were less sensitive. T-DM1 had limited activity. Unexpectedly, parental and ERBB2-knockout melanoma xenografts showed similar initial responses to T-DXd, although knockout tumors regrew earlier. Tumor-derived CTSL was detected outside melanoma cells in the xenografts. Melanoma cells were largely resistant to both ADCs in vitro and showed little trastuzumab uptake compared to HER2-amplified breast cancer cells. Conclusions: T-DXd has a substantial HER2-independent component of activity in the tested melanoma xenografts. Presence of extracellular CTSL, an enzyme known to cleave T-Dxd, provide a possibility that linker cleavage and payload release can occur outside of the tumor cells.",
  "abstract_shown": true,
  "affiliations": [
    "University of Gothenburg"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "L. M. Nilsson"
    },
    {
      "name": "E. S. Tanaydin"
    },
    {
      "name": "S. Stenqvist"
    },
    {
      "name": "D. Jansson"
    },
    {
      "name": "L. Ny"
    },
    {
      "affs": [
        0
      ],
      "name": "J. A. Nilsson"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fhc4azsg6jbw2.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.09.757939",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.09.757939v1.full",
  "id": "fhc4azsg6jbw2",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.09.757939v1",
  "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",
      "2730|HER2/EGFR in Cancer Research"
    ]
  ],
  "openalex": "W7221530789",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.09.757939v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-09",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/fhc4azsg6jbw2.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:27:19Z",
      "native_id": "10.64898/2026.10.09.757939",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.09.757939v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Trastuzumab deruxtecan kills skin and uveal melanoma in vivo by HER2-independent payload release",
  "title_text": "Trastuzumab deruxtecan kills skin and uveal melanoma in vivo by HER2-independent payload release",
  "type": "preprint",
  "updated_at": "2026-10-30T12:27:19Z",
  "url": "https://research.draconitic.com/paper/fhc4azsg6jbw2",
  "venue": "bioRxiv",
  "versions": []
}