{
  "abstract": "Triple-negative breast cancer (TNBC) is a highly metastatic and aggressive breast cancer subtype with limited targeted treatment options. Second mitochondrial activator of caspases (SMAC) mimetics represent a promising therapeutic class for TNBC patients, although they have yet to be approved clinically. Screening a repository of 69 breast cancer patient-derived xenograft organoid (PDxO) lines revealed that approximately 39% were sensitive to the SMAC mimetic birinapant. To define the basis of resistance in lines that did not respond, we compared birinapant-sensitive (S-) and de novo resistant (R-) TNBC PDxOs. Birinapant caused degradation of inhibitor of apoptosis proteins (IAPs) in both groups but failed to induce cell death in R-PDxOs. We determined that R-PDxOs were susceptible to certain types of apoptosis but were specifically resistant to TNFR-mediated cell death, an integral pathway involved in SMAC mimetic response. Moreover, RIPK1 activation via autophosphorylation, a critical event in TNFR-mediated apoptosis, was absent in both R-PDxOs and PDxOs selected for acquired birinapant resistance. Pharmacologic inhibition or degradation of RIPK1 protected S-PDxOs from birinapant-induced cell death, demonstrating that RIPK1 activation is required for response in TNBC. To investigate how to restore RIPK1 activation in R-PDxOs, we discovered that HOIP, an E3 ubiquitin ligase that inhibits RIPK1 autophosphorylation, was more abundant in R-PDxOs compared to S-PDxOs. Inhibiting HOIP activity restored RIPK1 autophosphorylation and sensitized a subset of R-PDxOs to birinapant. Together, these findings identify impaired RIPK1 autophosphorylation as a mechanism of birinapant resistance in TNBC and suggest that RIPK1 activation state may distinguish SMAC mimetic-sensitive and -resistant tumors. Targeting HOIP may provide a strategy to overcome resistance in selected tumors.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Oncological Sciences, University of Utah, 2000 Circle of Hope Dr, Salt Lake City, UT 84112",
    "Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Dr, Salt Lake City, UT 84112",
    "Department of Biomedical Informatics, University of Utah, 421 S Wakara Way #140, Salt Lake City, UT 84108",
    "Department of Pharmacology and Toxicology, University of Utah, 30 S 2000 E, Salt Lake City, UT 84112",
    "Applied and Developmental Research Directorate, Frederick National Laboratory, 1050 Boyles Street, Frederick, MD 21702",
    "Department of Surgery, University of Utah, 2000 Circle of Hope Dr, Salt Lake City, UT 84112"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Elisabeth Brown"
    },
    {
      "affs": [
        0
      ],
      "name": "Paige Jensen"
    },
    {
      "affs": [
        1
      ],
      "name": "Chieh-Hsiang Yang"
    },
    {
      "affs": [
        1
      ],
      "name": "Emilio Cortes Sanchez"
    },
    {
      "affs": [
        1
      ],
      "name": "Zhengtao Chu"
    },
    {
      "affs": [
        2
      ],
      "name": "Huiyi Yang"
    },
    {
      "affs": [
        2
      ],
      "name": "Yi Qiao"
    },
    {
      "affs": [
        1,
        3
      ],
      "name": "Martin Golkowski",
      "orcid": "0000-0002-8612-9598"
    },
    {
      "affs": [
        4
      ],
      "name": "Apurva Srivastava"
    },
    {
      "affs": [
        1,
        5
      ],
      "name": "Bryan E. Welm"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Jaime Fornetti"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Alana L. Welm"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5r86wwhcnrvz8.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.26.761582",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.26.761582v1.full",
  "id": "5r86wwhcnrvz8",
  "issns": [
    "2692-8205"
  ],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.26.761582v1",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "1312|Cell death mechanisms and regulation"
    ]
  ],
  "openalex": "W7224082177",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.26.761582v1.full.pdf",
  "pmcid": "PMC13733836",
  "pmid": "42990280",
  "published": "2026-10-26",
  "publisher": "Cold Spring Harbor Laboratory Preprints",
  "ris": "https://research.draconitic.com/paper/5r86wwhcnrvz8.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:30:12Z",
      "native_id": "10.64898/2026.10.26.761582",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.26.761582v1"
    },
    {
      "first_seen": "2026-11-08T12:23:32Z",
      "native_id": "PMC13733836",
      "source": "pmc",
      "url": "https://doi.org/10.64898/2026.10.26.761582"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Response to SMAC mimetics in patient-derived models of triple-negative breast cancer relies on RIPK1 activation",
  "title_text": "Response to SMAC mimetics in patient-derived models of triple-negative breast cancer relies on RIPK1 activation",
  "type": "preprint",
  "updated_at": "2026-11-08T12:23:32Z",
  "url": "https://research.draconitic.com/paper/5r86wwhcnrvz8",
  "venue": "bioRxiv",
  "versions": []
}