Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies

He, T.; Xiao, L.; Qiao, Y.; Klingbeil, O.; Young, E.; Wu, X. S.; Mannan, R.; Mahapatra, S.; Eyunni, S.; Tien, J. C.-Y.; Wang, X.; Zheng, Y.; Kim, N.; Zheng, H.; Hou, S.; Su, F.; Miner, S. J.; Mehra, R.; Cao, X.; Abbineni, C.; Samajdar, S.; Ramachandra, M.; Parolia, A.; Vakoc, C. R.; Chinnaiyan, A. M.

doi:10.1101/2024.01.22.576669

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bioRxiv · 10.1101/2024.01.22.576669

Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies

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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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He, T., Xiao, L., Qiao, Y., Klingbeil, O., Young, E., Wu, X. S., Mannan, R., Mahapatra, S., Eyunni, S., Tien, J. C.-Y., Wang, X., Zheng, Y., Kim, N., Zheng, H., Hou, S., Su, F., Miner, S. J., Mehra, R., Cao, X., Abbineni, C., Samajdar, S., Ramachandra, M., Parolia, A., Vakoc, C. R., Chinnaiyan, A. M.. 2024-01-25. Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies. https://doi.org/10.1101/2024.01.22.576669

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