Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies
The POU2F3-POU2AF2/3 (OCA-T1/2) transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we found that the POU2F3 molecular subtype of SCLC (SCLC-P) exhibits an exquisite dependence on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. SCLC-P cell lines were sensitive to nanomolar levels of a mSWI/SNF ATPase proteolysis targeting chimera (PROTAC) degrader when compared to other molecular subtypes of SCLC. POU2F3 and its cofactors were found to interact with components of the mSWI/SNF complex. The POU2F3 transcription factor complex was evicted from chromatin upon mSWI/SNF ATPase degradation, leading to attenuation of downstream oncogenic signaling in SCLC-P cells. A novel, orally bioavailable mSWI/SNF ATPase PROTAC degrader, AU-24118, demonstrated preferential efficacy in the SCLC-P relative to the SCLC-A subtype and significantly decreased tumor growth in preclinical models. AU-24118 did not alter normal tuft cell numbers in lung or colon, nor did it exhibit toxicity in mice. B cell malignancies which displayed a dependency on the POU2F1/2 cofactor, POU2AF1 (OCA-B), were also remarkably sensitive to mSWI/SNF ATPase degradation. Mechanistically, mSWI/SNF ATPase degrader treatment in multiple myeloma cells compacted chromatin, dislodged POU2AF1 and IRF4, and decreased IRF4 signaling. In a POU2AF1-dependent, disseminated murine model of multiple myeloma, AU-24118 enhanced survival compared to pomalidomide, an approved treatment for multiple myeloma. Taken together, our studies suggest that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
bioRxiv : the preprint server for biology - (2024) vom: 25. Jan. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
He, Tongchen [VerfasserIn] |
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| Links: |
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| Themen: |
IRF4 |
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| Anmerkungen: |
Date Revised 14.02.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2024.01.22.576669 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368174735 |
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| 520 | |a The POU2F3-POU2AF2/3 (OCA-T1/2) transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we found that the POU2F3 molecular subtype of SCLC (SCLC-P) exhibits an exquisite dependence on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. SCLC-P cell lines were sensitive to nanomolar levels of a mSWI/SNF ATPase proteolysis targeting chimera (PROTAC) degrader when compared to other molecular subtypes of SCLC. POU2F3 and its cofactors were found to interact with components of the mSWI/SNF complex. The POU2F3 transcription factor complex was evicted from chromatin upon mSWI/SNF ATPase degradation, leading to attenuation of downstream oncogenic signaling in SCLC-P cells. A novel, orally bioavailable mSWI/SNF ATPase PROTAC degrader, AU-24118, demonstrated preferential efficacy in the SCLC-P relative to the SCLC-A subtype and significantly decreased tumor growth in preclinical models. AU-24118 did not alter normal tuft cell numbers in lung or colon, nor did it exhibit toxicity in mice. B cell malignancies which displayed a dependency on the POU2F1/2 cofactor, POU2AF1 (OCA-B), were also remarkably sensitive to mSWI/SNF ATPase degradation. Mechanistically, mSWI/SNF ATPase degrader treatment in multiple myeloma cells compacted chromatin, dislodged POU2AF1 and IRF4, and decreased IRF4 signaling. In a POU2AF1-dependent, disseminated murine model of multiple myeloma, AU-24118 enhanced survival compared to pomalidomide, an approved treatment for multiple myeloma. Taken together, our studies suggest that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability | ||
| 650 | 4 | |a Preprint | |
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| 650 | 4 | |a small cell lung cancer (SCLC) | |
| 700 | 1 | |a Xiao, Lanbo |e verfasserin |4 aut | |
| 700 | 1 | |a Qiao, Yuanyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Klingbeil, Olaf |e verfasserin |4 aut | |
| 700 | 1 | |a Young, Eleanor |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Xiaoli S |e verfasserin |4 aut | |
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| 700 | 1 | |a Mahapatra, Somnath |e verfasserin |4 aut | |
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| 700 | 1 | |a Tien, Jean Ching-Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiaoju |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, NamHoon |e verfasserin |4 aut | |
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| 700 | 1 | |a Hou, Siyu |e verfasserin |4 aut | |
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| 700 | 1 | |a Miner, Stephanie J |e verfasserin |4 aut | |
| 700 | 1 | |a Mehra, Rohit |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Xuhong |e verfasserin |4 aut | |
| 700 | 1 | |a Sekhar, A Chandra |e verfasserin |4 aut | |
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| 700 | 1 | |a Vakoc, Christopher R |e verfasserin |4 aut | |
| 700 | 1 | |a Chinnaiyan, Arul M |e verfasserin |4 aut | |
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