靶向 POU2F-POU2AF 转录因子驱动的恶性肿瘤中的 mSWI/SNF 复合物。
Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies.
发表日期：2024 Aug 12
作者：
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
来源：
CANCER CELL
摘要：
POU2F3-POU2AF2/3 转录因子复合物是簇细胞谱系和簇细胞样小细胞肺癌 (SCLC) 的主要调节因子。在这里，我们确定了 SCLC (SCLC-P) 的 POU2F3 分子亚型对哺乳动物开关/蔗糖不可发酵 (mSWI/SNF) 染色质重塑复合物活性的特定依赖性。用 mSWI/SNF ATP 酶的蛋白水解靶向嵌合体 (PROTAC) 降解剂处理 SCLC-P 细胞，可将 POU2F3 及其共激活剂从染色质中驱逐出来，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 酶降解剂敏感，治疗会导致染色质驱逐 POU2AF1 和 IRF4，并减少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 酶降解剂可显着抑制 SCLC-P 和多发性骨髓瘤临床前模型中的肿瘤生长，且无毒性迹象。这项研究表明，POU2F-POU2AF 驱动的恶性肿瘤对 mSWI/SNF 复合物具有内在依赖性，代表治疗脆弱性。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。
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.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.