Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Small cell lung cancer (SCLC) comprises heterogeneous subtypes defined by transcription factors like ASCL1, NEUROD1, and POU2F3.
• POU2F3-positive SCLC, representing about 12% of cases, exhibits a specific dependency on the POU2F3 transcription factor, indicating potential therapeutic targets.

Approach:

• Genome-scale screens were employed to identify regulators of POU2F3 expression and SCLC proliferation.
• The study focused on defining the role of mSWI/SNF complexes, including non-canonical BAF (ncBAF) complexes, in POU2F3-positive SCLC.

Key Points:

• mSWI/SNF complexes were identified as critical dependencies specific to POU2F3-positive SCLC.
• Pharmacologic mSWI/SNF inhibition reduced proliferation in all tested POU2F3-positive SCLCs.
• Disruption of ncBAF via BRD9 degradation showed unique efficacy in pure non-neuroendocrine POU2F3-SCLCs.
• mSWI/SNF complexes maintain chromatin accessibility at key gene loci within POU2F3-mediated regulatory networks.

Conclusions:

• Targeting mSWI/SNF ATPases (SMARCA4/2) and BRD9 effectively reduced POU2F3-SCLC tumor growth and improved survival in vivo.
• mSWI/SNF complexes globally regulate the POU2F3 oncogenic program.
• mSWI/SNF inhibition presents a potential therapeutic strategy for POU2F3-positive SCLC.