Ellis Leigh, German Beatriz, Morel Katherine, Noel Teia, Boufaied Nadia, Burkhart Deborah, Chen Sujun, Dezem Felipe, Qiu Xintao, Long Henry, DiFazio Stefan, Baca Sylvan, Shafi Ayesha, Freedman Matthew, Beltran Himisha, Sweeney Christopher, He Housheng, Brown Myles, Plummer Jasmine, Knott Simon, Labbé David
Res Sq. 2025 Aug 21:rs.3.rs-7360528. doi: 10.21203/rs.3.rs-7360528/v1.
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 demonstrate that EZH2 regulates multilineage cell states dependent on the RNA binding protein Tristetraprolin (TTP) that mediates RNA stability and activation of translation. 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 or enzalutamide. 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.
表型可塑性是前列腺癌（PCa）中一种公认的治疗抵抗机制，然而目前对驱动机制和治疗干预的了解有限。利用缺乏Pten和Rb1的基因工程小鼠模型（GEMMs），我们之前证明了组蛋白重编程因子zeste同源物2（EZH2）增强子是促进表型可塑性的替代转录程序的重要调节因子。在这里，我们使用多组学方法证明，EZH2通过依赖于RNA结合蛋白三叶草四脯氨酸蛋白（TTP）来调节多谱系细胞状态，TTP介导RNA稳定性和翻译激活。EZH2和PI3K/mTORC1的联合化学抑制在小鼠和人类表型可塑性模型中产生了更强的抗肿瘤活性，当这种联合与去势或恩杂鲁胺一起使用时最为显著。总之，这些数据表明表型可塑性依赖于EZH2、TTP和mTORC1信号之间的协调，这代表了这种致命PCa表型的新型治疗依赖性。
