Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.
Cancer Res. 2024 Nov 4;84(21):3499-3501. doi: 10.1158/0008-5472.CAN-24-2913.
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.
治疗抵抗雄激素受体 (AR)-靶向药物仍然是前列腺癌治疗过程中的一个重大临床问题，随着越来越多的男性接受下一代 AR 靶向治疗，耐药疾病的发生率正在增加。谱系可塑性和向神经内分泌前列腺癌 (NEPC) 的进展是前列腺肿瘤失去对雄激素信号的依赖并逃避治疗的机制。尽管许多已知的遗传改变可能使肿瘤容易获得 NEPC 表型，但尚不清楚哪些驱动因素对这种进展是必不可少的。在本期《Cancer Research》中，Rodarte 及其同事鉴定出 ASCL1 是这样的一个必需调节因子。通过使用基因工程小鼠模型，作者证明尽管 ASCL1 对于肿瘤的形成和生长不是必需的，但 ASCL1 的缺失几乎完全阻止了 NEPC 的发展，而是将谱系轨迹重新定向为基底样表型。这项研究为 NEPC 的研究提供了一个重要的新模型，揭示了 ASCL1+NEPC 细胞也能够获得 NEUROD1+状态的能力，并证明了 ASCL1 缺失后肿瘤细胞表型的变化。请参阅 Rodarte 等人的相关文章，第 3522 页。
