Targeting m6A RNA epigenetics in treatment-emergent neuroendocrine prostate cancer

项目摘要/摘要 抗去势前列腺癌与临床、病理和分子水平显著相关 异质性：大多数肿瘤仍然由雄激素受体(AR)信号驱动，这具有临床意义 用于AR导向疗法的患者选择。然而，组织学和临床耐药表型也可以 在长时间的AR通路抑制后出现，肿瘤对AR信号的依赖程度降低 (被称为“雄激素冷漠”)。这些高度侵袭性和致命性的肿瘤被称为急诊治疗 神经内分泌前列腺癌(t-nepc)是由腺癌通过传代可塑性克隆性分化而来。 或转分化。对于t-NEPC，迫切需要新的靶点和治疗方法。T-NEPC细胞携带 反复发生的遗传和表观遗传变化作为一种适应性反应，从而表明关键分子 控制细胞命运的途径和驱动因素可能被用作治疗干预的靶点。N6- 甲基腺苷(M6A)是真核生物信使RNA中含量丰富的一种内部RNA修饰。尽管它的 不同类型癌症的功能重要性及其在前列腺癌进展和治疗中的特殊作用 抵抗仍然难以捉摸。我们对磷蛋白质组、表位转录组、转录组、 使用体外和体内模型的核糖体图谱确定m6A是令人兴奋的新表观遗传标记 潜在的前列腺癌谱系转变和治疗耐药。因此我们假设M6A 在前列腺癌中促进谱系可塑性并受抗雄激素的动态调节，以及靶向 M6A可以逆转t-NEPC的谱系转化，从而恢复对抗雄激素治疗的敏感性。 我们将通过追求以下具体目标来检验我们的中心假设：(1)确定泛函 M6A RNA表观遗传学在前列腺癌治疗耐药中的意义；(2)阐明 M6A在前列腺癌谱系可塑性和抗雄激素耐药中的作用机制 建立标记m6A的抑制剂治疗t-NEPC的治疗潜力。这样做的结果是 该项目有望为t-nepc疗法在将m6A rna表观遗传学与血统联系起来方面开辟新的途径。 可塑性介导的治疗抵抗，应该对我们解决 接受治疗的患者面临的最大挑战--新发恶性肿瘤。

Project Summary/Abstract Castration-resistant prostate cancer is associated with substantial clinical, pathologic, and molecular heterogeneity; most tumors remain driven by androgen receptor (AR) signaling, which has clinical implications for patient selection for AR-directed therapies. However, histologic and clinical resistance phenotypes can also emerge after prolonged AR pathway inhibition, in which the tumors become less dependent on AR signaling (referred to as ‘androgen indifferent’). These highly aggressive and lethal tumors, termed treatment-emergent neuroendocrine prostate cancer (t-NEPC), are clonally derived from adenocarcinoma through lineage plasticity or transdifferentiation. There is an urgent need for novel targets and therapies for t-NEPC. t-NEPC cells carry recurrent genetic and epigenetic alterations as an adaptive response, thus suggesting that key molecular pathways and drivers controlling cell fate may be used as targets for therapeutic intervention. N6- methyladenosine (m6A) is an abundant internal RNA modification in eukaryote messenger RNAs. Despite its functional importance in different types of cancer, their specific role in prostate cancer progression and therapy resistance still remains elusive. Our integrative analysis of phosphoproteome, epitranscriptome, transcriptome, and ribosome profiling using in vitro and in vivo models identified m6A as exciting new epigenetic mark underlying prostate cancer lineage transition and therapeutic resistance. We therefore hypothesize that m6A drives lineage plasticity and is dynamically regulated by antiandrogen in prostate cancer, and that targeting m6A can reverse the lineage transformation, thereby restoring sensitivity to antiandrogen therapy in t-NEPC. We will test our central hypothesis by pursuing the following specific aims: (1) Determine the functional significance of m6A RNA epigenetics for therapeutic resistance in prostate cancer; (2) Elucidate the molecular mechanisms of m6A function in prostate cancer lineage plasticity and antiandrogen resistance; and (3) Establish the therapeutic potential of inhibitors tageting m6A for treatment of t-NEPC. The outcomes of this project are expected to open new avenues for t-NEPC therapeutics in linking m6A RNA epigenetics to lineage plasticity-mediated therapy resistance, and should have a profound impact on our approach to tackle the greatest challenges facing patients with treatment-emergent maligancies.