Phenotypic plasticity is a hallmark of cancer and increasingly realized as a mechanism of resistance to androgen receptor (AR)-targeted therapy. Now that many prostate cancer (PCa) patients are treated upfront with AR-targeted agents, it's critical to identify actionable mechanisms that drive phenotypic plasticity, to prevent the emergence of resistance. We showed that loss of tristetraprolin (TTP, gene ZFP36) increased NF-κB activation, and was associated with higher rates of aggressive disease and early recurrence in primary PCa. We also examined the clinical and biological impact of ZFP36 loss with co-loss of PTEN, a known driver of PCa. Analysis of multiple independent primary PCa cohorts demonstrated that PTEN and ZFP36 co-loss was associated with increased recurrence risk. Engineering prostate-specific Zfp36 deletion in vivo, induced prostatic intraepithelial neoplasia, and, with Pten co-deletion, resulted in rapid progression to castration-resistant adenocarcinoma. Zfp36 loss altered the cell state driven by Pten loss, demonstrated by enrichment of EMT, inflammation, TNFα/NF-κB, IL6-JAK/STAT3 gene sets. Additionally, our work revealed that ZFP36 loss also induced enrichment of multiple gene sets involved in mononuclear cell migration, chemotaxis, and proliferation. Use of the NF-κB inhibitor, dimethylaminoparthenolide (DMAPT) induced marked therapeutic responses in tumors with PTEN and ZFP36 co-loss and reversed castration resistance.

中文翻译：

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低 tristetraprolin 表达激活表型可塑性，并引发小鼠转变为致命的前列腺癌。


表型可塑性是癌症的一个标志，并且越来越多地成为对雄激素受体 （AR） 靶向治疗耐药的机制。现在，许多前列腺癌 （PCa） 患者预先接受了 AR 靶向药物治疗，因此确定驱动表型可塑性的可操作机制以防止耐药性的出现至关重要。我们发现 tristetraprolin （TTP，基因 ZFP36） 的缺失增加了 NF-κB 的激活，并且与原发性 PCa 侵袭性疾病的发生率和早期复发率较高有关。我们还检查了 ZFP36 缺失与 PTEN 共同缺失（一种已知的 PCa 驱动因素）的临床和生物学影响。对多个独立原发性 PCa 队列的分析表明，PTEN 和 ZFP36 共同丢失与复发风险增加相关。体内工程化前列腺特异性 Zfp36 缺失，诱导前列腺上皮内瘤变，并且与 Pten 共缺失一起导致快速进展为去势抵抗性腺癌。Zfp36 缺失改变了 Pten 缺失驱动的细胞状态，表现为 EMT 、 炎症 、 TNFα/NF-κB 、 IL6-JAK/STAT3 基因集的富集。此外，我们的工作揭示了 ZFP36 缺失还诱导了参与单核细胞迁移、趋化性和增殖的多个基因集的富集。使用 NF-κB 抑制剂二甲氨基小蜜肠内酯 （DMAPT） 在 PTEN 和 ZFP36 共同丢失和逆转去势耐药的肿瘤中诱导显着的治疗反应。