Abstract C033: EZH2 regulates cell identity in neuroendocrine-like prostate cancer by driving alternate transcription via activation of translation and RNA processing regulation

Abstract Phenotypic plasticity is a recognized mechanism of therapeutic resistance in prostate cancer (PCa), however current knowledge of driver mechanisms and therapeutic interventions are 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 an important regulator of alternative transcription programs promoting phenotypic plasticity. Here, using a multi-omics approach we find that EZH2 regulates a multilineage cell state dependent on the activation of translation and regulation of RNA maturation. Combined chemical inhibition of EZH2 and PI3K/mTORC1 resulted in superior anti-tumor activity in murine and human phenotypic plastic models and was most significant when this combination was used with castration. Moreover, we elucidated that the regulation of cellular state transition by EZH2 inhibition requires activation of the RNA degrader, Tristetraprolin (TTP). Together, these data indicate phenotypic plasticity dependence on coordination between EZH2, TTP and mTORC1 signaling that represent novel therapeutic dependencies for this lethal PCa phenotype. Citation Format: Beatriz German, Leigh Ellis. EZH2 regulates cell identity in neuroendocrine-like prostate cancer by driving alternate transcription via activation of translation and RNA processing regulation [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C033.