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

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.