Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies
The POU2F3-POU2AF2/3 transcription factor complex plays a central role in regulating tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). In this study, we uncover a specific reliance of the POU2F3 molecular subtype of SCLC (SCLC-P) on the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Using a proteolysis targeting chimera (PROTAC) degrader to target mSWI/SNF ATPases in SCLC-P cells results in the displacement of AU-15330 POU2F3 and its coactivators from chromatin, leading to a reduction in downstream signaling. B cell malignancies reliant on the POU2F1/2 cofactor POU2AF1 also exhibit sensitivity to mSWI/SNF ATPase degraders, with treatment leading to the eviction of POU2AF1 and IRF4 from chromatin and reduced IRF4 signaling in multiple myeloma cells. An orally available mSWI/SNF ATPase degrader significantly curbs tumor growth in preclinical models of SCLC-P and multiple myeloma, showing no signs of toxicity. These findings indicate that POU2F-POU2AF-driven cancers have an inherent dependence on the mSWI/SNF complex, presenting a potential therapeutic target.