哥伦比亚大学瓦格洛斯内科和外科医学院Michael M. Shen研究团队近日取得一项新成果。经过不懈努力，他们提出了靶向NSD2逆转前列腺癌的可塑性和耐药。相关论文发表在2025年11月26日出版的《自然》杂志上。

本研究表明，通过抑制组蛋白甲基转移酶NSD2，可以逆转CRPC中可塑性相关的治疗抗性。CRPC-NE中NSD2的上调与不良的生存结果相关，NSD2介导的H3K36二甲基化调节与神经内分泌分化相关的基因增强子。在由基因工程小鼠建立的前列腺肿瘤类器官中（再现转分化到神经内分泌状态），以及在人类CRPC-NE类器官中，CRISPR介导的NSD2靶向使CRPC-NE恢复到腺癌表型。

此外，典型的AR程序被上调，对AR抑制剂enzalutamide的反应被恢复。在培养和异种移植物中，用一种首创的小分子药物抑制NSD2可逆转可塑性，并与enzalutamide协同抑制多种CRPC亚型的人类患者来源类器官的生长并促进细胞死亡。NSD2和AR的联合靶向可能代表了目前难以治疗的致死性CRPC的一种新的治疗策略。在临床前模型中，抑制组蛋白甲基转移酶NSD2和雄激素受体可以逆转谱系可塑性，从而抑制肿瘤生长并促进多种去势抵抗性前列腺癌亚型的细胞死亡。

据介绍，谱系可塑性是癌症的一个标志，它驱动疾病进展和治疗耐药性。可塑性通常是由可能可逆的表观遗传机制介导的；然而，这种可逆性的例子很少。在去势抵抗性前列腺癌（CRPC）中，可塑性介导了对雄激素受体（AR）抑制剂的抵抗，并从腺癌发展为侵袭性亚型，包括神经内分泌前列腺癌（CRPC-NE）。

附：英文原文

Title: NSD2 targeting reverses plasticity and drug resistance in prostate cancer

Author: Li, Jia J., Vasciaveo, Alessandro, Karagiannis, Dimitris, Sun, Zhen, Gretarsson, Kristjan H., Chen, Xiao, Ouerfelli, Ouathek, Socciarelli, Fabio, Frankenstein, Ziv, Dong, Hanyang, Zou, Min, Yuan, Wei, Yang, Guangli, Aizenman, Gabriel M., Pannellini, Tania, Xu, Xinjing, Beltran, Himisha, Chen, Yu, Gardner, Kevin, Robinson, Brian D., de Bono, Johann, Gozani, Or, Abate-Shen, Cory, Rubin, Mark A., Loda, Massimo, Sawyers, Charles L., Califano, Andrea, Lu, Chao, Shen, Michael M.

Issue&Volume: 2025-11-26

Abstract: Lineage plasticity is a cancer hallmark that drives disease progression and treatment resistance1,2. Plasticity is often mediated by epigenetic mechanisms that may be reversible; however, there are few examples of such reversibility. In castration-resistant prostate cancer (CRPC), plasticity mediates resistance to androgen receptor (AR) inhibitors and progression from adenocarcinoma to aggressive subtypes, including neuroendocrine prostate cancer (CRPC-NE)3–5. Here we show that plasticity-associated treatment resistance in CRPC can be reversed through the inhibition of NSD2, a histone methyltransferase6. NSD2 upregulation in CRPC-NE correlates with poor survival outcomes, and NSD2-mediated H3K36 dimethylation regulates enhancers of genes associated with neuroendocrine differentiation. In prostate tumour organoids established from genetically engineered mice7 that recapitulate the transdifferentiation to neuroendocrine states, and in human CRPC-NE organoids, CRISPR-mediated targeting of NSD2 reverts CRPC-NE to adenocarcinoma phenotypes. Moreover, a canonical AR program is upregulated and responses to the AR inhibitor enzalutamide are restored. Pharmacological inhibition of NSD2 with a first-in-class small molecule reverses plasticity and synergizes with enzalutamide to suppress growth and promote cell death in human patient-derived organoids of multiple CRPC subtypes in culture and in xenografts. Co-targeting of NSD2 and AR may represent a new therapeutic strategy for lethal forms of CRPC that are currently recalcitrant to treatment. Inhibition of the histone methyltransferase NSD2 and the androgen receptor in preclinical models can reverse lineage plasticity to suppress tumour growth and promote cell death in multiple subtypes of castration-resistant prostate cancer.

DOI: 10.1038/s41586-025-09727-z

Source: https://www.nature.com/articles/s41586-025-09727-z