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

Duplaquet, L.; So, K.; Ying, A. W.; Li, X.; Li, Y.; Qiu, X.; Li, R.; Singh, S.; Wu, X. S.; Liu, Q.; Qi, J.; Somerville, T. D. D.; Heiling, H.; Mazzola, E.; Lee, Y.; Zoller, T.; Vakoc, C. R.; Doench, J. G.; Forrester, W. C.; Abrams, T.; Long, H. W.; Niederst, M. J.; Kadoch, C.; Oser, M. G.

doi:10.1101/2024.01.21.576304

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bioRxiv · 10.1101/2024.01.21.576304

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

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Abstract

Small cell lung cancers (SCLC) are comprised of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLC, [~]12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes, including non-canonical BAF (ncBAF) complexes, as top dependencies specific to POU2F3-positive SCLC. Notably, clinical-grade pharmacologic mSWI/SNF inhibition attenuates proliferation of all POU2F3-positive SCLCs, while disruption of ncBAF via BRD9 degradation is uniquely effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, chemical targeting of SMARCA4/2 mSWI/SNF ATPases and BRD9 decrease POU2F3-SCLC tumor growth and increase survival in vivo. Taken together, these results characterize mSWI/SNF-mediated global governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for SCLC.

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Duplaquet, L., So, K., Ying, A. W., Li, X., Li, Y., Qiu, X., Li, R., Singh, S., Wu, X. S., Liu, Q., Qi, J., Somerville, T. D. D., Heiling, H., Mazzola, E., Lee, Y., Zoller, T., Vakoc, C. R., Doench, J. G., Forrester, W. C., Abrams, T., Long, H. W., Niederst, M. J., Kadoch, C., Oser, M. G.. 2024-01-24. Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer. https://doi.org/10.1101/2024.01.21.576304

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