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 approximately 12% of cases, exhibits a specific dependence on the POU2F3 transcription factor.

Purpose of the Study:

• To identify regulators of POU2F3 expression and SCLC proliferation using genome-scale screens.
• To explore mSWI/SNF complexes as potential therapeutic targets in POU2F3-positive SCLC.

Main Methods:

• Genome-scale screens to identify regulators of POU2F3 expression and SCLC proliferation.
• Chemical disruption of mSWI/SNF ATPase activity and BRD9 degradation.
• In vivo studies using clinical-grade pharmacologic agents targeting SMARCA4/2 ATPases and BRD9.

Main Results:

• mSWI/SNF complexes were identified as key dependencies specific to POU2F3-positive SCLC.
• Inhibition of mSWI/SNF ATPase activity reduced proliferation in all POU2F3-positive SCLCs.
• BRD9 degradation effectively targeted non-canonical BAF (ncBAF) in pure non-neuroendocrine POU2F3-SCLCs.
• mSWI/SNF complexes regulate gene accessibility in POU2F3-mediated networks.
• Pharmacologic inhibition decreased tumor growth and increased survival in vivo.

Conclusions:

• mSWI/SNF complexes are central to the POU2F3 oncogenic program in SCLC.
• Targeting mSWI/SNF complexes, including ncBAF, represents a promising therapeutic strategy for POU2F3-positive SCLC.