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)
Preview |
PDF
10.1016.j.ccell.2024.06.006.pdf - Published Version Available under License Creative Commons Attribution. Download (9MB) | Preview |
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: | |
| 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: | |
| Dataset ID: | |
| URI: | https://repository.cshl.edu/id/eprint/41621 |
Actions (login required)
 |
Administrator's edit/view item |