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

Area of Science:

• Oncology
• Molecular Biology
• Chromatin Biology

Background:

• The POU2F3-POU2AF2/3 complex regulates tuft cell and small cell lung cancer (SCLC) lineages.
• POU2F3-driven SCLC (SCLC-P) and POU2F1/2-driven B cell malignancies represent distinct cancer subtypes.

Purpose of the Study:

• To investigate the dependence of SCLC-P and B cell malignancies on the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex.
• To evaluate the therapeutic potential of mSWI/SNF ATPase degraders in these cancers.

Main Methods:

• Utilized proteolysis targeting chimera (PROTAC) degraders targeting mSWI/SNF ATPases.
• Assessed the effect of degraders on transcription factor eviction from chromatin and downstream signaling.
• Tested an orally bioavailable mSWI/SNF ATPase degrader in preclinical models of SCLC-P and multiple myeloma.

Main Results:

• mSWI/SNF ATPase degraders evicted POU2F3 and coactivators from chromatin in SCLC-P cells, attenuating signaling.
• Treatment also led to chromatin eviction of POU2AF1 and IRF4 in multiple myeloma cells, decreasing IRF4 signaling.
• An orally bioavailable degrader significantly inhibited tumor growth in SCLC-P and multiple myeloma models with no observed toxicity.

Conclusions:

• POU2F-POU2AF-driven malignancies exhibit a specific dependence on mSWI/SNF complex activity.
• Targeting mSWI/SNF ATPases with degraders represents a promising therapeutic strategy for SCLC-P and multiple myeloma.