Targeting m6A RNA epigenetics in treatment-emergent neuroendocrine prostate cancer

项目概要/摘要 去势抵抗性前列腺癌与实质性的临床、病理和分子生物学特征相关。 异质性;大多数肿瘤仍然由雄激素受体（AR）信号传导驱动，这具有临床意义 用于选择AR导向治疗的患者。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，其中肿瘤变得不太依赖于AR信号传导 （被称为“雄激素无关”）。这些高度侵袭性和致命性的肿瘤，称为治疗后出现的肿瘤， 神经内分泌前列腺癌（t-NEPC）是通过谱系可塑性从腺癌克隆衍生而来的 或转分化。迫切需要针对t-NEPC的新靶点和疗法。t-NEPC细胞携带 周期性遗传和表观遗传改变作为适应性反应，从而表明，关键分子 控制细胞命运的途径和驱动器可用作治疗干预的靶。N6- 甲基腺苷（m6 A）是真核生物信使RNA中丰富的内部RNA修饰。尽管 在不同类型癌症中的功能重要性，它们在前列腺癌进展和治疗中的特定作用 抵抗仍然是难以捉摸的。我们对磷酸化蛋白质组，表转录组，转录组， 使用体外和体内模型的核糖体分析将m6 A鉴定为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抗性。因此，我们假设m6 A 驱动谱系可塑性，并在前列腺癌中受抗雄激素的动态调节， m6 A可以逆转谱系转化，从而恢复t-NEPC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测试我们的中心假设：（1）确定功能 m6 A RNA表观遗传学在前列腺癌治疗耐药中的意义;（2）阐明m6 A RNA表观遗传学在前列腺癌治疗耐药中的分子作用。 m6 A在前列腺癌谱系可塑性和抗雄激素抗性中的功能机制;和（3） 确定标记m6 A的抑制剂治疗t-NEPC的治疗潜力。这个结果 该项目有望为t-NEPC治疗开辟新的途径，将m6 A RNA表观遗传学与谱系联系起来 可塑性介导的治疗耐药性，并应该对我们的方法产生深远的影响，以解决 治疗后出现的恶性肿瘤患者面临的最大挑战。

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.