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Updated: Sep 9, 2025

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EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer

Leigh Ellis1,2,3, Beatriz German4, Katherine Morel5

  • 1Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

Research Square
|September 2, 2025
PubMed

Insights

Phenotypic plasticity in prostate cancer (PCa) drives resistance. Targeting enhancer of zeste homolog 2 (EZH2) and PI3K/mTORC1 shows promise against this lethal PCa subtype.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Phenotypic plasticity is a key mechanism of therapeutic resistance in prostate cancer (PCa).
  • Limited knowledge exists regarding the drivers and therapeutic interventions for PCa phenotypic plasticity.
  • Enhancer of zeste homolog 2 (EZH2) was previously identified as a regulator of alternative transcription programs in PCa.

Purpose of the Study:

  • To elucidate the mechanisms driving phenotypic plasticity in prostate cancer.
  • To investigate the role of RNA binding protein Tristetraprolin (TTP) in EZH2-mediated plasticity.
  • To evaluate combination therapies for targeting therapy-resistant PCa.

Main Methods:

  • Utilized genetically engineered mouse models (GEMMs) lacking Pten and Rb1.
  • Employed a multi-omics approach to analyze molecular changes.
  • Assessed the efficacy of combined chemical inhibition of EZH2 and PI3K/mTORC1.

Main Results:

  • EZH2 regulates multilineage cell states dependent on Tristetraprolin (TTP).
  • TTP mediates RNA stability and translation activation.
  • Combined inhibition of EZH2 and PI3K/mTORC1 demonstrated superior anti-tumor activity in murine and human models.
  • This combination therapy was most effective when used with castration or enzalutamide.

Conclusions:

  • Phenotypic plasticity in lethal PCa is dependent on the coordination between EZH2, TTP, and mTORC1 signaling.
  • This coordination represents a novel therapeutic dependency for treating therapy-resistant PCa.
  • Combination therapy targeting EZH2 and PI3K/mTORC1 offers a promising strategy against lethal prostate cancer.
Keywords:
EZH2PI3KPhenotypic PlasticityTranslationmTOR

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