Cancer cell · 2024
Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
He Tongchen, Xiao Lanbo, Qiao Yuanyuan, Klingbeil Olaf, Young Eleanor, Wu Xiaoli S, Mannan Rahul, Mahapatra Somnath, Redin Esther, Cho Hanbyul, Bao Yi, Kandarpa Malathi, Ching-Yi Tien Jean, Wang Xiaoju, Eyunni Sanjana, Zheng Yang, Kim NamHoon, Zheng Heng, Hou Siyu, Su Fengyun, Miner Stephanie J, Mehra Rohit, Cao Xuhong, Abbineni Chandrasekhar, Samajdar Susanta, Ramachandra Murali, Dhanasekaran Saravana M, Talpaz Moshe, Parolia Abhijit, Rudin Charles M, Vakoc Christopher R, Chinnaiyan Arul M
Аннотация
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.