美国密歇根大学Arul M. Chinnaiyan团队近期取得重要工作进展，他们研究提出可以通过靶向mSWI/SNF复合体来治疗POU2F-POU2AF转录因子驱动的恶性肿瘤。相关研究成果2024年7月18日在线发表于《癌细胞》杂志上。

据介绍，POU2F3-POU2AF2/3转录因子复合物是簇状细胞谱系和簇细胞样小细胞肺癌（SCLC）的主要调节因子。

研究人员发现了SCLC的POU2F3分子亚型（SCLC-P）对哺乳动物mSWI/SNF染色质重塑复合物活性的特定依赖性。用蛋白水解靶向嵌合体（PROTAC）mSWI/SNF ATPases降解器处理SCLC-P细胞，可将POU2F3及其辅助激活因子从染色质中驱逐出去，并减弱下游信号传导。

依赖于POU2F1/2辅因子POU2AF1的B细胞恶性肿瘤也对mSWI/SNF-ATP酶降解物敏感，治疗导致POU2AF2和IRF4的染色质排出，并降低多发性骨髓瘤细胞中的IRF4信号传导。口服生物可利用的mSWI/SNF-ATP酶降解剂在SCLC-P和多发性骨髓瘤的临床前模型中显著抑制肿瘤生长，没有毒性迹象。

总之，这一研究表明，POU2F-POU2AF驱动的恶性肿瘤对mSWI/SNF复合物具有内在的依赖性，这代表了一种治疗脆弱性。

附：英文原文

Title: Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies

Author: Tongchen He, Lanbo Xiao, Yuanyuan Qiao, Olaf Klingbeil, Eleanor Young, Xiaoli S. Wu, Rahul Mannan, Somnath Mahapatra, Esther Redin, Hanbyul Cho, Yi Bao, Malathi Kandarpa, Jean Ching-Yi Tien, Xiaoju Wang, Sanjana Eyunni, Yang Zheng, NamHoon Kim, Heng Zheng, Siyu Hou, Fengyun Su, Stephanie J. Miner, Rohit Mehra, Xuhong Cao, Chandrasekhar Abbineni, Susanta Samajdar, Murali Ramachandra, Saravana M. Dhanasekaran, Moshe Talpaz, Abhijit Parolia, Charles M. Rudin, Christopher R. Vakoc, Arul M. Chinnaiyan

Issue&Volume: 2024-07-18

Abstract: The POU2F3-POU2AF2/3 transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we identify a specific dependence of the POU2F3 molecular subtype of SCLC (SCLC-P) on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Treatment of SCLC-P cells with a proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases evicts POU2F3 and its coactivators from chromatin and attenuates downstream signaling. B cell malignancies which are dependent on the POU2F1/2 cofactor, POU2AF1, are also sensitive to mSWI/SNF ATPase degraders, with treatment leading to chromatin eviction of POU2AF1 and IRF4 and decreased IRF4 signaling in multiple myeloma cells. An orally bioavailable mSWI/SNF ATPase degrader significantly inhibits tumor growth in preclinical models of SCLC-P and multiple myeloma without signs of toxicity. This study suggests that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.

DOI: 10.1016/j.ccell.2024.06.006

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(24)00231-9