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

Area of Science:

• Oncology
• Molecular Biology
• Chromatin Biology

Background:

• The POU2F3 transcription factor complex regulates tuft cell development and tuft cell-like small cell lung cancer (SCLC).
• POU2F3-driven cancers, specifically SCLC-P, show a unique dependency on the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex.

Approach:

• Investigated the sensitivity of SCLC-P cell lines to mSWI/SNF ATPase proteolysis targeting chimera (PROTAC) degraders.
• Examined the interaction between POU2F3 and mSWI/SNF complex components.
• Assessed the efficacy of a novel mSWI/SNF ATPase PROTAC degrader, AU-24118, in preclinical SCLC-P and multiple myeloma models.

Key Points:

• SCLC-P cell lines were highly sensitive to mSWI/SNF ATPase degradation, leading to POU2F3 eviction from chromatin and reduced oncogenic signaling.
• AU-24118 demonstrated preferential efficacy in SCLC-P models and improved survival in a multiple myeloma model, outperforming an approved drug.
• POU2F-POU2AF-driven B cell malignancies also exhibited sensitivity to mSWI/SNF ATPase degradation, with mechanistic insights into chromatin compaction and transcription factor displacement.

Conclusions:

• POU2F-POU2AF-driven cancers, including SCLC-P and certain B cell malignancies, possess an exploitable dependence on the mSWI/SNF chromatin remodeling complex.
• mSWI/SNF ATPase degradation represents a promising therapeutic strategy for these malignancies, with AU-24118 showing significant preclinical efficacy and a favorable safety profile.