2025年10月20日出版的《自然—遗传学》杂志发表了丹娜-法伯癌症研究所Cigall Kadoch团队的最新成果，他们的研究开发出了mSWI/SNF家族亚复合物的组装和功能的改变是去分化子宫内膜癌中靶向依赖性的基础。

在细胞模型和原发性人类肿瘤中，课题组研究人员发现ARID1A和/或ARID1B （ARID1A/B）缺陷介导的cBAF损失导致ncBAF和PBAF生化丰度和染色质水平功能增加，以维持DDEC的致癌状态。

此外，使用临床级SMARCA4和/或SMARCA2 ATP酶抑制剂治疗可显著降低体内DDEC细胞增殖和肿瘤生长，并与基于卡铂的化疗协同作用以延长生存期。这些发现揭示了mSWI/SNF家族复杂化学计量变化和由此导致的基因调控失调的致癌作用，并提示mSWI/SNF小分子抑制剂在DDEC/ UECs和其他cBAF破坏的癌症类型中的治疗作用。

据了解，哺乳动物(m)SWI/SNF家族染色质重塑因子控制细胞类型特异性染色质可及性和基因表达，并组装成三种不同的复合物：典型BRG1相关或BRM相关因子（cBAF），多溴相关BAF （PBAF）和非典型BAF （ncBAF）。ARID1A和ARID1B是平行亚基，特异地为cBAF复合物组装成核，在高度侵袭性去分化或未分化子宫内膜癌（DDEC/UECs）中经常发生共突变。

附：英文原文

Title: Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in dedifferentiated endometrial carcinomas

Author: St. Laurent, Jessica D., Xu, Grace D., Ying, Alexander W., Gokbayrak, Bengul, Patil, Ajinkya, Paulo, Joao A., Cervantes, Kasey S., Chen, Shary, Feng, William W., Sankar, Akshay, Sam Guerra, Daniel D., Qi, Jun, Neel, Dana S., Hornick, Jason L., Kolin, David L., Gygi, Steven P., Hunstman, David G., Wang, Yemin, Kadoch, Cigall

Issue&Volume: 2025-10-20

Abstract: The mammalian (m)SWI/SNF family of chromatin remodelers govern cell type-specific chromatin accessibility and gene expression and assemble as three distinct complexes: canonical BRG1-associated or BRM-associated factor (cBAF), poly(bromo)-associated BAF (PBAF) and noncanonical BAF (ncBAF). ARID1A and ARID1B are paralog subunits that specifically nucleate the assembly of cBAF complexes and are frequently co-mutated in highly aggressive dedifferentiated or undifferentiated endometrial carcinomas (DDEC/UECs). Here in cellular models and primary human tumors, we find that ARID1A and/or ARID1B (ARID1A/B) deficiency-mediated cBAF loss results in increased ncBAF and PBAF biochemical abundance and chromatin-level functions to maintain the DDEC oncogenic state. Furthermore, treatment with clinical-grade SMARCA4 and/or SMARCA2 ATPase inhibitors markedly attenuates DDEC cell proliferation and tumor growth in vivo and synergizes with carboplatin-based chemotherapy to extend survival. These findings reveal the oncogenic contributions of shifted mSWI/SNF family complex stoichiometry and resulting gene-regulatory dysregulation and suggest therapeutic utility of mSWI/SNF small molecule inhibitors in DDEC/UECs and other cBAF-disrupted cancer types.

DOI: 10.1038/s41588-025-02333-9

Source: https://www.nature.com/articles/s41588-025-02333-9