哺乳动物 SWI/SNF 复合物活性调节 POU2F3 并构成小细胞肺癌的靶向依赖性。
Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer.
发表日期：2024 Aug 12
作者：
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
来源：
CANCER CELL
摘要：
小细胞肺癌 (SCLC) 由具有谱系特异性转录因子标记的异质亚型组成，包括 ASCL1、NEUROD1 和 POU2F3。 POU2F3 阳性 SCLC 占所有病例的 12%，唯一依赖于 POU2F3 本身；因此，减弱 POU2F3 表达的方法可能代表新的治疗机会。在这里，我们使用基因组规模筛选 POU2F3 表达和 SCLC 增殖的调节因子，将 mSWI/SNF 复合物定义为 POU2F3 阳性 SCLC 特有的首要依赖性。值得注意的是，化学破坏 mSWI/SNF ATPase 活性会减弱所有 POU2F3 阳性 SCLC 的增殖，而通过 BRD9 降解破坏非典型 BAF (ncBAF) 对纯非神经内分泌 POU2F3-SCLC 有效。 mSWI/SNF 针对 POU2F3 介导的基因调控网络的核心基因位点并维持其可访问性。最后，SMARCA4/2 ATPase 和 BRD9 的临床级药理破坏可降低 POU2F3-SCLC 肿瘤生长并提高体内存活率。这些结果证明了 mSWI/SNF 介导的 POU2F3 致癌程序的治理，并表明 mSWI/SNF 抑制可作为 POU2F3 阳性 SCLC 的治疗策略。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。
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.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.