{
  "abstract": "Phenotypic plasticity is a recognized mechanism of therapeutic resistance in prostate cancer (PCa); however, current knowledge of its underlying drivers and therapeutic interventions remain limited. Using genetically engineered mouse models (GEMMs) devoid of Pten and Rb1, we previously demonstrated the chromatin reprogramming factor enhancer of zeste homolog 2 (EZH2) as a regulator of alternative transcription programs promoting phenotypic plasticity. Here, using a multi-omics approach, we demonstrate that EZH2 regulates multilineage cell states and identify the RNA-binding protein Tristetraprolin (TTP) as a contributor to the response to EZH2 therapy through its role in RNA stability and translational regulation. Combined pharmacological inhibition of EZH2 and PI3K/mTORC1 produces superior antitumor activity in murine and human models of phenotypic plasticity, with greatest efficacy observed when combined with castration. Together, these findings identify EZH2-PI3K/mTORC1 signaling as a therapeutic vulnerability in phenotypically plastic PCa and reveal TTP-associated regulatory programs as contributors to targeted therapy response.",
  "abstract_shown": true,
  "affiliations": [
    "Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA",
    "The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA",
    "Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA",
    "South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, SA, Australia",
    "Cedars-Sinai Center for Bioinformatics and Functional Genomics, Los Angeles, CA, USA",
    "Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC, Canada",
    "Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA",
    "West China School of Public Health, West China Fourth Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China",
    "Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA",
    "Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA",
    "Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA",
    "Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada",
    "Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada",
    "Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA",
    "Division of Urology, Department of Surgery, McGill University, Montréal, QC, Canada"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 22,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Beatriz German"
    },
    {
      "affs": [
        3
      ],
      "name": "Katherine L. Morel"
    },
    {
      "affs": [
        4
      ],
      "name": "Teia Noel"
    },
    {
      "affs": [
        5
      ],
      "name": "Nadia Boufaied"
    },
    {
      "affs": [
        6
      ],
      "name": "Deborah L. Burkhart"
    },
    {
      "affs": [
        7
      ],
      "name": "Sujun Chen"
    },
    {
      "affs": [
        8
      ],
      "name": "Felipe Dezem"
    },
    {
      "affs": [
        9,
        10
      ],
      "name": "Xintao Qiu"
    },
    {
      "affs": [
        9,
        10
      ],
      "name": "Henry W. Long"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Kun-Lin Ho"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Stefan DiFazio"
    },
    {
      "affs": [
        10
      ],
      "name": "Sylvan Baca"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Ayesha A. Shafi"
    },
    {
      "affs": [
        9,
        10
      ],
      "name": "Matthew L. Freedman"
    },
    {
      "affs": [
        10
      ],
      "name": "Himisha Beltran"
    },
    {
      "affs": [
        3
      ],
      "name": "Christopher J. Sweeney"
    },
    {
      "affs": [
        11,
        12
      ],
      "name": "Housheng Hansen He"
    },
    {
      "affs": [
        9,
        10
      ],
      "name": "Myles Brown"
    },
    {
      "affs": [
        8
      ],
      "name": "Jasmine T. Plummer"
    },
    {
      "affs": [
        4,
        13
      ],
      "name": "Simon.R.V. Knott"
    },
    {
      "affs": [
        5,
        14
      ],
      "name": "David P. Labbé"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Leigh Ellis"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/42er57v2t4278.bib",
  "cited_by": 0,
  "doi": "10.1016/j.xcrm.2026.103083",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13710546/",
  "id": "42er57v2t4278",
  "issns": [
    "2666-3791"
  ],
  "landing_url": "https://doi.org/10.1016/j.xcrm.2026.103083",
  "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": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2740|Prostate Cancer Treatment and Research"
    ]
  ],
  "openalex": "W7214974219",
  "pdf_url": null,
  "pmcid": "PMC13710546",
  "pmid": "42815467",
  "published": "2026-09-30",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/42er57v2t4278.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:21:30Z",
      "native_id": "PMC13710546",
      "source": "pmc",
      "url": "https://doi.org/10.1016/j.xcrm.2026.103083"
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2740|Prostate Cancer Treatment and Research",
      "subfield": "general"
    }
  ],
  "title": "EZH2-dependent phenotypic plasticity reveals TTP-associated and mTORC1 therapeutic vulnerabilities in lethal prostate cancer",
  "title_text": "EZH2-dependent phenotypic plasticity reveals TTP-associated and mTORC1 therapeutic vulnerabilities in lethal prostate cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:21:30Z",
  "url": "https://research.draconitic.com/paper/42er57v2t4278",
  "venue": "Cell Reports Medicine",
  "versions": []
}