斯坦福大学Or Gozani课题组宣布他们的最新研究探明了NSD2抑制剂重新连接染色质治疗肺癌和胰腺癌。相关论文于2025年8月6日发表在《自然》杂志上。

在这里，该团队描述了一系列临床级小分子催化NSD2抑制剂（NSD2i），并表明在KRAS驱动的临床前癌症模型中，NSD2的药理学靶向构成了一种具有广泛治疗效果的表观遗传依赖性。NSD2i对NSD2具有个位数纳摩尔半最大抑制浓度效力和对相关甲基转移酶的高选择性。结构分析表明，NSD2i对NSD2的特异性是由于与S-腺苷蛋氨酸的竞争性结合和通过二元通道阻塞机制的催化破坏。胰腺癌和肺癌模型中的蛋白质-表观基因组学和单细胞策略支持一种机制，其中持续的NSD2i暴露逆转病理性H3K36me2驱动的染色质可塑性，重新建立H3K27me3遗传位点的沉默，以减少致癌基因表达程序。因此，NSD2i损害胰腺癌和肺癌细胞的活力以及患者来源的异种移植肿瘤的生长。

此外，在体内耐受性良好的NSD2i，延长了晚期自体免疫性KRAS^G12C驱动的胰腺和肺肿瘤的生存期，其水平与sotorasib6的KRAS抑制水平相当。在这些模型中，使用NSD2抑制剂和sotorasib进行治疗，可以通过广泛的肿瘤消退和消除来获得持续的生存。总之，他们的工作揭示了靶向NSD2–H3K36me2轴是难以治疗的癌症的可操作脆弱性，并为临床环境中NSD2和KRAS抑制剂联合治疗的评估提供了支持。

研究人员表示，NSD2催化表观遗传修饰H3K36me2，并且是多种恶性肿瘤中致癌信号传导的候选下游趋同效应物。然而，目前尚不清楚NSD2的酶活性是否具有治疗靶向性。

附：英文原文

Title: NSD2 inhibitors rewire chromatin to treat lung and pancreatic cancers

Author: Jeong, Jinho, Hausmann, Simone, Dong, Hanyang, Szczepski, Kacper, Flores, Natasha M., Garcia Gonzalez, Andy, Shi, Liyang, Lu, Xiaoyin, Lempiinen, Joanna, Jakab, Moritz, Zeng, Liyong, Chasan, Tourkian, Bareke, Eric, Dong, Rui, Carlson, Emma, Padilla, Reinnier, Husmann, Dylan, Thompson, Julia, Shipman, Gerry A., Zahn, Emily, Barnes, Courtney A., Khan, Laiba F., Albertorio-Sez, Liz Marie, Brill, Eva, Kumary, Vishnu Udayakumar Sunita, Marunde, Matthew R., Maryanski, Danielle N., Szany, Cheryl C., Venters, Bryan J., Windham, Carolina Lin, Nowakowski, Michal Eligiusz, Czaban, Iwona, Jaremko, Mariusz, Keogh, Michael-Christopher, Le, Kang, Soth, Michael J., Garcia, Benjamin A., Jaremko, ukasz, Majewski, Jacek, Mazur, Pawel K., Gozani, Or

Issue&Volume: 2025-08-06

Abstract: NSD2 catalyses the epigenetic modification H3K36me2 (refs. 1,2) and is a candidate convergent downstream effector of oncogenic signalling in diverse malignancies3,4,5. However, it remains unclear whether the enzymatic activity of NSD2 is therapeutically targetable. Here we characterize a series of clinical-grade small-molecule catalytic NSD2 inhibitors (NSD2i) and show that the pharmacological targeting of NSD2 constitutes an epigenetic dependency with broad therapeutic efficacy in KRAS-driven preclinical cancer models. NSD2i inhibits NSD2 with single-digit nanomolar half-maximal inhibitory concentration potency and high selectivity over related methyltransferases. Structural analyses reveal that the specificity of NSD2i for NSD2 is due to competitive binding with S-adenosylmethionine and catalytic disruption through a binary-channel obstruction mechanism. Proteo-epigenomic and single-cell strategies in pancreatic and lung cancer models support a mechanism in which sustained NSD2i exposure reverses pathological H3K36me2-driven chromatin plasticity, re-establishing silencing at H3K27me3-legacy loci to curtail oncogenic gene expression programs. Accordingly, NSD2i impairs the viability of pancreatic and lung cancer cells and the growth of patient-derived xenograft tumours. Furthermore, NSD2i, which is well-tolerated in vivo, prolongs survival in advanced-stage autochthonous KRASG12C-driven pancreatic and lung tumours in mouse models to a comparable level as KRAS inhibition with sotorasib6. In these models, treatment with both a NSD2 inhibitor and sotorasib synergize to confer sustained survival with extensive tumour regression and elimination. Together, our work uncovers targeting of the NSD2–H3K36me2 axis as an actionable vulnerability in difficult to treat cancers and provides support for the evaluation of NSD2 and KRAS inhibitor combination therapies in a clinical setting.

DOI: 10.1038/s41586-025-09299-y

Source: https://www.nature.com/articles/s41586-025-09299-y