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

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. [Display omitted] •mSWI/SNF complex and its ATPase subunit are epigenetic dependencies in SCLC-P•POU2F3 complex requires the mSWI/SNF complex to modulate chromatin accessibility•POU2AF1 and IRF4 function as an epigenetic complex requiring mSWI/SNF in MM•An oral mSWI/SNF ATPase degrader shows potent anti-tumor efficacy in SCLC-P and MM He et al. reveal a promising avenue of treatment for small cell lung cancer and multiple myeloma driven by POU2F/POU2AF. The study highlights the potential of targeting the mSWI/SNF complex to impede oncogenic POU2F/POU2AF signaling and tumor growth, offering hope for improved therapies in these aggressive cancer types.