Therapeutic resistance to androgen receptor (AR)–targeting agents remains a significant clinical problem during the treatment of prostate cancer, with the incidence rate of resistant disease increasing as more men are treated with next-generation AR-targeted therapies. Lineage plasticity and progression to neuroendocrine prostate cancer (NEPC) are mechanisms by which prostate tumors lose dependence on androgen signaling and escape treatment. Although many known genetic alterations can predispose tumors to acquiring the NEPC phenotype, it remains unclear what, if any, drivers are essential to this progression. In this issue of Cancer Research, Rodarte and colleagues identified ASCL1 as one such essential regulator. Through the use of genetically engineered mouse models, the authors demonstrated that whereas ASCL1 was dispensable for tumor formation and growth, ASCL1 loss nearly completely abrogated the development of NEPC and instead redirected lineage trajectories toward a basal-like phenotype. This study provides an important new model for the study of NEPC, reveals the ability of ASCL1+ NEPC cells to also assume a NEUROD1+ state, and demonstrates the changes to tumor cell phenotypes following ASCL1 loss. See related article by Rodarte et al., p. 3522

中文翻译：

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ASCL1 驱动神经内分泌前列腺癌的发展


在前列腺癌治疗过程中，对雄激素受体 （AR） 靶向药物的治疗耐药性仍然是一个重要的临床问题，随着越来越多的男性接受下一代 AR 靶向治疗，耐药性疾病的发生率会增加。谱系可塑性和进展为神经内分泌前列腺癌 （NEPC） 是前列腺肿瘤失去对雄激素信号传导和逃逸治疗的依赖性的机制。尽管许多已知的基因改变可使肿瘤易患 NEPC 表型，但目前尚不清楚哪些驱动因素（如果有）对这种进展至关重要。在本期《癌症研究》中，Rodarte 及其同事将 ASCL1 确定为这样一种重要的调节因子。通过使用基因工程小鼠模型，作者证明，虽然 ASCL1 对于肿瘤形成和生长是可有可无的，但 ASCL1 缺失几乎完全消除了 NEPC 的发展，而是将谱系轨迹重定向到基础样表型。本研究为 NEPC 的研究提供了一个重要的新模型，揭示了 ASCL1+ NEPC 细胞也具有 NEUROD1+ 状态的能力，并展示了 ASCL1 缺失后肿瘤细胞表型的变化。参见 Rodarte 等人的相关文章，第 3522 页