He, Tongchen, Xiao, Lanbo, Qiao, Yuanyuan, Klingbeil, Olaf, Young, Eleanor, Wu, Xiaoli S, Mannan, Rahul, Mahapatra, Somnath, Eyunni, Sanjana, Tien, Jean Ching-Yi, Wang, Xiaoju, Zheng, Yang, Kim, NamHoon, Zheng, Heng, Hou, Siyu, Su, Fengyun, Miner, Stephanie J, Mehra, Rohit, Cao, Xuhong, Sekhar, A Chandra, Samajdar, Susanta, Ramachandra, Murali, Parolia, Abhijit, Vakoc, Christopher R, Chinnaiyan, Arul M (January 2024) Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies. bioRxiv. (Submitted)
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Abstract
The POU2F3-POU2AF2/3 (OCA-T1/2) transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we found that the POU2F3 molecular subtype of SCLC (SCLC-P) exhibits an exquisite dependence on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. SCLC-P cell lines were sensitive to nanomolar levels of a mSWI/SNF ATPase proteolysis targeting chimera (PROTAC) degrader when compared to other molecular subtypes of SCLC. POU2F3 and its cofactors were found to interact with components of the mSWI/SNF complex. The POU2F3 transcription factor complex was evicted from chromatin upon mSWI/SNF ATPase degradation, leading to attenuation of downstream oncogenic signaling in SCLC-P cells. A novel, orally bioavailable mSWI/SNF ATPase PROTAC degrader, AU-24118, demonstrated preferential efficacy in the SCLC-P relative to the SCLC-A subtype and significantly decreased tumor growth in preclinical models. AU-24118 did not alter normal tuft cell numbers in lung or colon, nor did it exhibit toxicity in mice. B cell malignancies which displayed a dependency on the POU2F1/2 cofactor, POU2AF1 (OCA-B), were also remarkably sensitive to mSWI/SNF ATPase degradation. Mechanistically, mSWI/SNF ATPase degrader treatment in multiple myeloma cells compacted chromatin, dislodged POU2AF1 and IRF4, and decreased IRF4 signaling. In a POU2AF1-dependent, disseminated murine model of multiple myeloma, AU-24118 enhanced survival compared to pomalidomide, an approved treatment for multiple myeloma. Taken together, our studies suggest that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.
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