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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Phenotypic plasticity is a key mechanism of therapeutic resistance in prostate cancer (PCa).
• The specific molecular drivers and effective therapeutic interventions for plastic PCa remain incompletely understood.
• Enhancer of zeste homolog 2 (EZH2) has been identified as a regulator of alternative transcription programs that promote phenotypic plasticity.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying EZH2-driven phenotypic plasticity in prostate cancer.
• To investigate the role of RNA binding protein Tristetraprolin (TTP) in mediating EZH2's regulation of cell states.
• To evaluate the therapeutic efficacy of combined EZH2 and PI3K/mTORC1 inhibition, alone and with standard therapies, in preclinical models of PCa.

Main Methods:

• Utilized genetically engineered mouse models (GEMMs) lacking Pten and Rb1.
• Employed a multi-omics approach to analyze molecular changes.
• Assessed anti-tumor activity of combined chemical inhibition of EZH2 and PI3K/mTORC1 in murine and human PCa models.

Main Results:

• Demonstrated that EZH2 regulates multilineage cell states dependent on Tristetraprolin (TTP).
• Showed that TTP mediates RNA stability and translation activation.
• Found superior anti-tumor activity with combined EZH2 and PI3K/mTORC1 inhibition in plastic PCa models.
• Observed enhanced efficacy when the combination therapy was administered with castration or enzalutamide.

Conclusions:

• Phenotypic plasticity in lethal prostate cancer is critically dependent on the coordinated function of EZH2, TTP, and mTORC1 signaling.
• This coordination represents a novel therapeutic vulnerability in advanced prostate cancer.
• Combined inhibition of EZH2 and PI3K/mTORC1, particularly with enzalutamide, shows significant promise for treating resistant PCa phenotypes.