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Peer-reviewedCC BY 4.0Cell Reports Medicine

EZH2-dependent phenotypic plasticity reveals TTP-associated and mTORC1 therapeutic vulnerabilities in lethal prostate cancer

  • Beatriz German1,2,3
  • Katherine L. Morel4
  • Teia Noel5
  • Nadia Boufaied6
  • Deborah L. Burkhart7
  • Sujun Chen8
  • Felipe Dezem9
  • Xintao Qiu10,11
  • Henry W. Long10,11
  • Kun-Lin Ho1,2
  • Stefan DiFazio1,2
  • Sylvan Baca11
10 more authors
  • Ayesha A. Shafi1,2
  • Matthew L. Freedman10,11
  • Himisha Beltran11
  • Christopher J. Sweeney4
  • Housheng Hansen He12,13
  • Myles Brown10,11
  • Jasmine T. Plummer9
  • Simon.R.V. Knott5,14
  • David P. Labbé6,15
  • Leigh Ellis1,2,3
15 affiliations
  1. 1Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
  2. 2The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA
  3. 3Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
  4. 4South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, SA, Australia
  5. 5Cedars-Sinai Center for Bioinformatics and Functional Genomics, Los Angeles, CA, USA
  6. 6Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
  7. 7Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
  8. 8West China School of Public Health, West China Fourth Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
  9. 9Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA
  10. 10Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
  11. 11Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
  12. 12Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
  13. 13Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
  14. 14Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
  15. 15Division of Urology, Department of Surgery, McGill University, Montréal, QC, Canada
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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.

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Cite

BibTeXRIS
BibTeX
@article{german2026ezh2dependent,
  title = {{EZH2-dependent phenotypic plasticity reveals TTP-associated and mTORC1 therapeutic vulnerabilities in lethal prostate cancer}},
  author = {Beatriz German and Katherine L. Morel and Teia Noel and Nadia Boufaied and Deborah L. Burkhart and Sujun Chen and Felipe Dezem and Xintao Qiu and Henry W. Long and Kun-Lin Ho and Stefan DiFazio and Sylvan Baca and Ayesha A. Shafi and Matthew L. Freedman and Himisha Beltran and Christopher J. Sweeney and Housheng Hansen He and Myles Brown and Jasmine T. Plummer and Simon.R.V. Knott and David P. Labbé and Leigh Ellis},
  journal = {Cell Reports Medicine},
  year = {2026},
  month = sep,
  doi = {10.1016/j.xcrm.2026.103083},
  url = {https://doi.org/10.1016/j.xcrm.2026.103083},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - EZH2-dependent phenotypic plasticity reveals TTP-associated and mTORC1 therapeutic vulnerabilities in lethal prostate cancer
AU  - Beatriz German
AU  - Katherine L. Morel
AU  - Teia Noel
AU  - Nadia Boufaied
AU  - Deborah L. Burkhart
AU  - Sujun Chen
AU  - Felipe Dezem
AU  - Xintao Qiu
AU  - Henry W. Long
AU  - Kun-Lin Ho
AU  - Stefan DiFazio
AU  - Sylvan Baca
AU  - Ayesha A. Shafi
AU  - Matthew L. Freedman
AU  - Himisha Beltran
AU  - Christopher J. Sweeney
AU  - Housheng Hansen He
AU  - Myles Brown
AU  - Jasmine T. Plummer
AU  - Simon.R.V. Knott
AU  - David P. Labbé
AU  - Leigh Ellis
PY  - 2026
DA  - 2026/09/30
JO  - Cell Reports Medicine
DO  - 10.1016/j.xcrm.2026.103083
UR  - https://doi.org/10.1016/j.xcrm.2026.103083
AB  - 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.
SN  - 2666-3791
ER  -