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

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 (June 2024) Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies. Cancer Cell. S1535-6108(24)00231. ISSN 1535-6108 (Public Dataset)

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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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > lung cancer diseases & disorders > cancer > cancer types > small cell lung cancer diseases & disorders > cancer > cancer types
CSHL Authors:	Klingbeil, Olaf Vakoc, Christopher R.
Communities:	CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL labs > Vakoc lab CSHL Cancer Center Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	26 June 2024
Date Deposited:	23 Jul 2024 14:19
Last Modified:	23 Jul 2024 14:19
Related URLs:	Publisher
Dataset ID:	GEO: GSE247951
URI:	https://repository.cshl.edu/id/eprint/41621

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