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, Samé Guerra Daniel D, Qi Jun, Neel Dana S, Hornick Jason L, Kolin David L, Gygi Steven P, Hunstman David G, Wang Yemin, Kadoch Cigall
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nat Genet. 2025 Oct 20. doi: 10.1038/s41588-025-02333-9.
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.
哺乳动物染色质重塑因子（m）SWI/SNF家族调控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：经典的BRG1相关或BRM相关因子（cBAF）、多溴相关BAF（PBAF）和非经典BAF（ncBAF）。ARID1A和ARID1B是旁系同源亚基，它们特异性地启动cBAF复合物的组装，并且在高度侵袭性的去分化或未分化子宫内膜癌（DDEC/UECs）中经常同时发生突变。在细胞模型和原发性人类肿瘤中，我们发现ARID1A和/或ARID1B（ARID1A/B）缺陷介导的cBAF缺失导致ncBAF和PBAF生化丰度及染色质水平功能增加，以维持DDEC的致癌状态。此外，临床级SMARCA4和/或SMARCA2 ATP酶抑制剂治疗可显著减弱DDEC细胞增殖和体内肿瘤生长，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家族复合物化学计量改变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效用。
