{
  "abstract": "Resistance to standard-of-care therapies remains a major clinical challenge in the treatment of the most common breast cancer, the hormone receptor-positive (HR+) subtype. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors improve outcomes in early-stage HR+ disease, yet many patients relapse. Resistance mechanisms of relapsed tumors include genetic alterations, but in many cases, no genetic drivers are identified. Here, we investigated mechanisms underlying resistance to CDK4/6 inhibitors using breast cancer patient-derived models and tumors. We identified an unexpected, noncanonical nuclear function of fumarylacetoacetate hydrolase (FAH), an enzyme in the tyrosine catabolism pathway, as a driver of resistance. FAH translocated to the nucleus upon CDK4/6 inhibition, where it interacted with cyclin-dependent kinase 9 (CDK9), and promoted resistance. Nuclear FAH was enriched in tumors from relapsed patients, and inhibition of CDK9 reversed FAH-mediated resistance. These findings establish nuclear FAH as a biomarker of resistance and revealed CDK9 as a therapeutic vulnerability in CDK4/6 inhibitor-resistant HR+ breast cancer.",
  "abstract_shown": true,
  "affiliations": [
    "Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.",
    "Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.",
    "Core Facilities, Medical University of Vienna, Vienna, Austria.",
    "Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.",
    "Department of Physiology and Biophysics, University of Illinois Cancer Center, University of Illinois College of Medicine, Chicago, IL, USA.",
    "Department of Pathology, and Laboratory Medicine, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, USA."
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 20,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jenny Högström",
      "orcid": "0000-0001-5932-0146"
    },
    {
      "affs": [
        0
      ],
      "name": "Hanna M. Doh",
      "orcid": "0000-0003-0781-611X"
    },
    {
      "affs": [
        0
      ],
      "name": "Aidan Kump",
      "orcid": "0009-0002-6491-578X"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Boryana Petrova",
      "orcid": "0000-0001-9996-9353"
    },
    {
      "affs": [
        1
      ],
      "name": "Peng Wang",
      "orcid": "0000-0001-8118-4929"
    },
    {
      "affs": [
        0
      ],
      "name": "Jonathan D. Lee",
      "orcid": "0000-0002-1229-0098"
    },
    {
      "affs": [
        0
      ],
      "name": "Kaisa Koivula",
      "orcid": "0009-0007-9055-3897"
    },
    {
      "affs": [
        0
      ],
      "name": "Nina Kozlova",
      "orcid": "0000-0002-4944-7917"
    },
    {
      "affs": [
        0
      ],
      "name": "Kayla A. Cruz",
      "orcid": "0000-0001-8880-5804"
    },
    {
      "affs": [
        0
      ],
      "name": "Su Min Hong",
      "orcid": "0009-0006-8472-9924"
    },
    {
      "affs": [
        0
      ],
      "name": "Camila Perea",
      "orcid": "0009-0002-1159-4863"
    },
    {
      "affs": [
        1
      ],
      "name": "Arjun Garg",
      "orcid": "0009-0003-1676-630X"
    },
    {
      "affs": [
        1
      ],
      "name": "Michal Weitman",
      "orcid": "0000-0001-8061-3840"
    },
    {
      "affs": [
        3
      ],
      "name": "Conor L. Evans",
      "orcid": "0000-0003-2185-6505"
    },
    {
      "affs": [
        4
      ],
      "name": "Jonathan L. Coloff",
      "orcid": "0000-0003-4726-3097"
    },
    {
      "affs": [
        0
      ],
      "name": "Jaymin M. Patel"
    },
    {
      "affs": [
        0
      ],
      "name": "Gerburg M. Wulf",
      "orcid": "0000-0001-7868-6231"
    },
    {
      "affs": [
        5
      ],
      "name": "Laura C. Collins"
    },
    {
      "affs": [
        1
      ],
      "name": "Naama Kanarek",
      "orcid": "0000-0002-2068-3908"
    },
    {
      "affs": [
        0
      ],
      "name": "Taru Muranen",
      "orcid": "0000-0003-4158-9002"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3x12j0dy0tb8x.bib",
  "cited_by": 0,
  "doi": "10.1126/sciadv.aef1145",
  "fulltext_url": null,
  "id": "3x12j0dy0tb8x",
  "issns": [
    "2375-2548"
  ],
  "landing_url": "https://www.science.org/doi/10.1126/sciadv.aef1145",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2740|Advanced Breast Cancer Therapies"
    ]
  ],
  "openalex": "W7214921910",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-02",
  "publisher": "American Association for the Advancement of Science (AAAS)",
  "ris": "https://research.draconitic.com/paper/3x12j0dy0tb8x.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:41Z",
      "native_id": "10.1126/sciadv.aef1145",
      "source": "crossref",
      "url": "https://www.science.org/doi/10.1126/sciadv.aef1145"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2740|Advanced Breast Cancer Therapies",
      "subfield": "general"
    }
  ],
  "title": "A noncanonical function of the tyrosine degradation enzyme FAH drives CDK4/6 inhibitor resistance in breast cancer",
  "title_text": "A noncanonical function of the tyrosine degradation enzyme FAH drives CDK4/6 inhibitor resistance in breast cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:41Z",
  "url": "https://research.draconitic.com/paper/3x12j0dy0tb8x",
  "venue": "Science Advances",
  "versions": []
}