美国丹娜-法伯癌症研究所Matthew G. Oser和Cigall Kadoch小组的研究显示，哺乳动物SWI/SNF复合物参与调控POU2F3并且小细胞肺癌（SCLCs）对其具有靶向依赖性。2024年7月18日出版的《癌细胞》发表了这项成果。

研究人员利用基因组规模筛选来寻找调控POU2F3表达和SCLC增殖的调控因子，发现POU2F3阳性SCLC对mSWI/SNF复合物具有特异且最高的依赖性。值得注意的是，通过化学方法破坏mSWI/SNF的ATPase活性，可减弱所有POU2F3阳性SCLC的增殖，而通过降解BRD9破坏非典型BAF (ncBAF)，则对纯合的非神经内分泌POU2F3-SCLC有效。

最后，对SMARCA4/2 ATP酶和BRD9进行临床级别的药物干扰，可减少POU2F3-SCLC肿瘤的生长并提高个体存活率。这些结果阐明了mSWI/SNF通过调控POU2F3致癌的机制，并说明抑制mSWI/SNF可作为POU2F3阳性SCLC的治疗策略。

研究人员表示，小细胞肺癌由不同亚型组成，其特征是存在特异的转录因子，包括ASCL1、NEUROD1和POU2F3。POU2F3阳性的SCLC（占所有病例的12%）对POU2F3本身具有独特的依赖性，因此，减少POU2F3表达的方法可能是一种新的治疗方法。

附：英文原文

Title: Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer

Author: Leslie Duplaquet, Kevin So, Alexander W. Ying, Shreoshi Pal Choudhuri, Xinyue Li, Grace D. Xu, Yixiang Li, Xintao Qiu, Rong Li, Shilpa Singh, Xiaoli S. Wu, Seth Hamilton, Victor D. Chien, Qi Liu, Jun Qi, Tim D.D. Somerville, Hillary M. Heiling, Emanuele Mazzola, Yenarae Lee, Thomas Zoller, Christopher R. Vakoc, John G. Doench, William C. Forrester, Tinya Abrams, Henry W. Long, Matthew J. Niederst, Benjamin J. Drapkin, Cigall Kadoch, Matthew G. Oser

Issue&Volume: 2024-07-18

Abstract: Small cell lung cancers (SCLCs) are composed of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLCs, ～12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes as top dependencies specific to POU2F3-positive SCLC. Notably, chemical disruption of mSWI/SNF ATPase activity attenuates proliferation of all POU2F3-positive SCLCs, while disruption of non-canonical BAF (ncBAF) via BRD9 degradation is effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF targets to and maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, clinical-grade pharmacologic disruption of SMARCA4/2 ATPases and BRD9 decreases POU2F3-SCLC tumor growth and increases survival in vivo. These results demonstrate mSWI/SNF-mediated governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for POU2F3-positive SCLCs.

DOI: 10.1016/j.ccell.2024.06.012

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(24)00237-X