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

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.