SCI
9 August 2024
Mammalian SWI/SNF complex activity regulate POU2F3 and constitutes a targetable dependency in small cell lung cancer
(Cancer Cell, IF: 48.8)
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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, and Matthew G. Oser
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CORRESPONDENCE To: cigall_kadoch@dfci.harvard.edu, matthew_oser@dfci.harvard.edu
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.
小细胞肺癌（SCLCs）由以谱系特异性转录因子为标志的异质亚型组成，包括ASCL1、NEUROD1和POU2F3。POU2F3阳性小细胞肺癌，占所有病例的12%，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的筛选来筛得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特有的顶级依赖性。值得注意的是，mSWI/SNF ATP酶活性的化学破坏会减弱所有POU2F3阳性小细胞肺癌的增殖，而通过BRD9降解破坏非规范BAF（ncBAF）在纯非神经内分泌POU2F3小细胞肺癌中是有效的。mSWI/SNF靶向并维持对POU2F3介导的基因调控网络核心基因座的可及性。最后，SMARCA4/2 ATP酶和BRD9的临床级药理学破坏可降低POU2F3-SCLC肿瘤的生长并提高体内存活率。这些结果证明了mSWI/SNF介导的POU2F3致癌程序的调控，并表明mSWI/SMF抑制是POU2F3阳性小细胞肺癌的一种治疗策略。