Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer
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 survivalin 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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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 27. Jan. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Duplaquet, Leslie [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2024.01.21.576304 |
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| PPN (Katalog-ID): |
XBI042272270 |
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| 245 | 1 | 0 | |a Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer |
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| 520 | |a 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 survivalin 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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| 700 | 1 | |a So, Kevin |4 aut | |
| 700 | 1 | |a Ying, Alexander W. |4 aut | |
| 700 | 1 | |a Li, Xinyue |4 aut | |
| 700 | 1 | |a Li, Yixiang |4 aut | |
| 700 | 1 | |a Qiu, Xintao |0 (orcid)0000-0002-8560-7017 |4 aut | |
| 700 | 1 | |a Li, Rong |4 aut | |
| 700 | 1 | |a Singh, Shilpa |4 aut | |
| 700 | 1 | |a Wu, Xiaoli S. |4 aut | |
| 700 | 1 | |a Liu, Qi |4 aut | |
| 700 | 1 | |a Qi, Jun |4 aut | |
| 700 | 1 | |a Somerville, Tim D.D. |4 aut | |
| 700 | 1 | |a Heiling, Hillary |4 aut | |
| 700 | 1 | |a Mazzola, Emanuele |4 aut | |
| 700 | 1 | |a Lee, Yenarae |4 aut | |
| 700 | 1 | |a Zoller, Thomas |4 aut | |
| 700 | 1 | |a Vakoc, Christopher R. |4 aut | |
| 700 | 1 | |a Doench, John G. |4 aut | |
| 700 | 1 | |a Forrester, William C. |4 aut | |
| 700 | 1 | |a Abrams, Tinya |4 aut | |
| 700 | 1 | |a Long, Henry W. |0 (orcid)0000-0001-6849-6629 |4 aut | |
| 700 | 1 | |a Niederst, Matthew J. |4 aut | |
| 700 | 1 | |a Kadoch, Cigall |4 aut | |
| 700 | 1 | |a Oser, Matthew G. |0 (orcid)0000-0003-2047-0969 |4 aut | |
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