{
  "abstract": "Cancers depend on transcriptional control to maintain the malignant cell state. EP300 and CBP are paralogous master epigenetic enzymes that control normal and malignant transcription. Using a cancer-wide integrative chemical-genetic analysis, we demonstrate enhanced dependency on EP300, compared with CBP, in cell lines from most cancer lineages, including lethal osteosarcoma (OS). Using a selective EP300 degrader (JQAD1), we identify that a genetically defined subgroup of OS with dysregulation of the PI3K–AKT–mTOR pathway is genetically and chemically sensitive to loss of EP300. Activated AKT promotes sensitivity to JQAD1, driven by relocalization of EP300, CBP and H3K27ac to genetic subtype-enriched dependency loci. AKT inhibition combines with JQAD1 to synergistically suppress the growth of AKT-dysregulated OS cells in vitro and in orthotopic xenografts. These observations extend across >850 cancer cell lines, where synergy is predicted by elevated protein synthetic rates. These findings reveal determinants of EP300 degrader function in OS and provide a foundation for co-targeting EP300 and AKT in cancers with enhanced protein translation.",
  "abstract_shown": true,
  "affiliations": [
    "Division of Molecular Oncology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.",
    "Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.",
    "Nantes Université , INSERM UMR 1307, CNRS UMR 6075, CRCI2NA, Nantes, France.",
    "Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA.",
    "St. Jude Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital , Memphis, TN, USA.",
    "Broad Institute of MIT and Harvard , Cambridge, MA, USA.",
    "Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.",
    "Division of Pediatric Oncology, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 33,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Ian M Delahunty"
    },
    {
      "affs": [
        0
      ],
      "name": "Stephanie Nance",
      "orcid": "0009-0007-9597-2134"
    },
    {
      "affs": [
        1
      ],
      "name": "Yang Zhang",
      "orcid": "0000-0003-1712-7211"
    },
    {
      "affs": [
        2
      ],
      "name": "Francois Lamoureux",
      "orcid": "0000-0002-2738-0758"
    },
    {
      "affs": [
        3
      ],
      "name": "Qi Liu",
      "orcid": "0000-0002-4100-9509"
    },
    {
      "affs": [
        1
      ],
      "name": "William C Wright",
      "orcid": "0000-0002-2274-9966"
    },
    {
      "affs": [
        0
      ],
      "name": "K Elaine Ritter",
      "orcid": "0000-0002-5586-5154"
    },
    {
      "affs": [
        0
      ],
      "name": "Noha A M Shendy",
      "orcid": "0000-0002-4765-6774"
    },
    {
      "affs": [
        2
      ],
      "name": "Bénédicte Brounais-Le Roye",
      "orcid": "0000-0002-4556-9853"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Sandra J Kietlinska",
      "orcid": "0000-0002-5775-559X"
    },
    {
      "affs": [
        0
      ],
      "name": "Mohammad A Mohammad Nezhady",
      "orcid": "0000-0001-6022-6632"
    },
    {
      "affs": [
        1
      ],
      "name": "Yuan Feng",
      "orcid": "0009-0007-8932-4405"
    },
    {
      "affs": [
        5
      ],
      "name": "Barbara De Kegel",
      "orcid": "0000-0002-4194-234X"
    },
    {
      "affs": [
        5
      ],
      "name": "Matthew G Rees",
      "orcid": "0000-0002-2987-7581"
    },
    {
      "affs": [
        5
      ],
      "name": "Mustafa Kocak",
      "orcid": "0009-0003-9681-5975"
    },
    {
      "affs": [
        5
      ],
      "name": "Ashish B George",
      "orcid": "0000-0002-6923-3596"
    },
    {
      "affs": [
        6
      ],
      "name": "Meifen Lu",
      "orcid": "0009-0007-9828-0694"
    },
    {
      "affs": [
        6
      ],
      "name": "Anoop M Kavirayani",
      "orcid": "0000-0003-3874-3101"
    },
    {
      "affs": [
        1
      ],
      "name": "Bo Wang",
      "orcid": "0009-0005-0756-2019"
    },
    {
      "affs": [
        1
      ],
      "name": "Yanling Liu",
      "orcid": "0000-0002-4244-2742"
    },
    {
      "affs": [
        0
      ],
      "name": "Paris E A Prinsen",
      "orcid": "0009-0000-5019-6943"
    },
    {
      "affs": [
        0
      ],
      "name": "Yousef Khashana",
      "orcid": "0009-0008-6338-2583"
    },
    {
      "affs": [
        0
      ],
      "name": "Vernon Justice Ebegboni",
      "orcid": "0000-0002-1898-6555"
    },
    {
      "affs": [
        5
      ],
      "name": "Melissa M Ronan",
      "orcid": "0000-0003-4269-1404"
    },
    {
      "affs": [
        5
      ],
      "name": "Jennifer A Roth",
      "orcid": "0000-0002-5117-5586"
    },
    {
      "affs": [
        7
      ],
      "name": "E Alejandro Sweet-Cordero",
      "orcid": "0000-0002-9787-9351"
    },
    {
      "affs": [
        0
      ],
      "name": "Lillian M Guenther",
      "orcid": "0000-0002-5906-7504"
    },
    {
      "affs": [
        1
      ],
      "name": "Paul Geeleher",
      "orcid": "0000-0002-5128-0087"
    },
    {
      "affs": [
        1
      ],
      "name": "Xiaotu Ma",
      "orcid": "0000-0002-6233-2145"
    },
    {
      "affs": [
        2
      ],
      "name": "Benjamin Ory",
      "orcid": "0000-0002-2622-7356"
    },
    {
      "affs": [
        3
      ],
      "name": "Jun Qi",
      "orcid": "0000-0002-1461-3356"
    },
    {
      "affs": [
        1,
        4
      ],
      "name": "Brian J Abraham",
      "orcid": "0000-0001-8085-3027"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Adam D Durbin",
      "orcid": "0000-0002-5472-9847"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/acsqv81ceq4pa.bib",
  "cited_by": 0,
  "doi": "10.1084/jem.20251898",
  "fulltext_url": "https://europepmc.org/articles/PMC13682445",
  "id": "acsqv81ceq4pa",
  "issns": [
    "0022-1007",
    "1540-9538"
  ],
  "landing_url": "https://hal.science/hal-05829036v1",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
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      "1312|Protein Degradation and Inhibitors"
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  "pdf_url": "https://hal.science/hal-05829036/document",
  "pmcid": "PMC13682445",
  "pmid": "42900185",
  "published": "2026-10-20",
  "publisher": "Rockefeller University Press",
  "ris": "https://research.draconitic.com/paper/acsqv81ceq4pa.ris",
  "sources": [
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Degradation and Inhibitors",
      "subfield": "molecular-biology"
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  ],
  "title": "Dysregulated AKT signaling reprograms osteosarcoma to drive selective reliance on EP300",
  "title_text": "Dysregulated AKT signaling reprograms osteosarcoma to drive selective reliance on EP300",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:32Z",
  "url": "https://research.draconitic.com/paper/acsqv81ceq4pa",
  "venue": "Journal of Experimental Medicine",
  "versions": []
}