Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies Journal Article
| Authors: | He, T.; Xiao, L.; Qiao, Y.; Klingbeil, O.; Young, E.; Wu, X. S.; Mannan, R.; Mahapatra, S.; Redin, E.; Cho, H.; Bao, Y.; Kandarpa, M.; Ching-Yi Tien, J.; Wang, X.; Eyunni, S.; Zheng, Y.; Kim, N.; Zheng, H.; Hou, S.; Su, F.; Miner, S. J.; Mehra, R.; Cao, X.; Abbineni, C.; Samajdar, S.; Ramachandra, M.; Dhanasekaran, S. M.; Talpaz, M.; Parolia, A.; Rudin, C. M.; Vakoc, C. R.; Chinnaiyan, A. M. |
| Article Title: | Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies |
| Abstract: | The POU2F3-POU2AF2/3 transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we identify a specific dependence of the POU2F3 molecular subtype of SCLC (SCLC-P) on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Treatment of SCLC-P cells with a proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases evicts POU2F3 and its coactivators from chromatin and attenuates downstream signaling. B cell malignancies which are dependent on the POU2F1/2 cofactor, POU2AF1, are also sensitive to mSWI/SNF ATPase degraders, with treatment leading to chromatin eviction of POU2AF1 and IRF4 and decreased IRF4 signaling in multiple myeloma cells. An orally bioavailable mSWI/SNF ATPase degrader significantly inhibits tumor growth in preclinical models of SCLC-P and multiple myeloma without signs of toxicity. This study suggests that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability. © 2024 The Author(s) |
| Keywords: | signal transduction; controlled study; aged; unclassified drug; human cell; genetics; cisplatin; drug potentiation; nonhuman; antineoplastic agent; ubiquitin; animal cell; mouse; animal; metabolism; animals; mice; proteasome; multiple myeloma; protein degradation; etoposide; lung neoplasms; animal experiment; animal model; transcription factor; in vivo study; antineoplastic activity; in vitro study; tumor xenograft; drug screening; pathology; xenograft model antitumor assays; cell line, tumor; protein p53; transcription factors; lung tumor; gene expression regulation; cancer inhibition; gene expression regulation, neoplastic; immunocytochemistry; chromatin; chromatin immunoprecipitation; myc protein; tumor cell line; western blotting; immunoblotting; tumor suppressor protein; bmi1 protein; dna extraction; octamer transcription factor 4; octamer transcription factor-3; genomic dna; histone deacetylase; interferon regulatory factor 4; carfilzomib; small cell lung cancer; small cell lung carcinoma; nucleosome; sclc; brm protein; brg1 protein; pomalidomide; polycomb repressive complex 2; vinculin; octamer transcription factor 2; humans; human; article; octamer transcription factor-2; rb1 protein; tunel assay; swi/snf related matrix associated actin dependent regulator of chromatin subfamily b member 1; pou2f3; irf4; protac; proteolysis targeting chimera; mswi/snf complex; pou2af1/2/3; smarca2/4; au 15330; au 24118; transcription factor pou2af; pou2f2 protein, human; smarca2 protein, human; nci-h526 cell line |
| Journal Title: | Cancer Cell |
| Volume: | 42 |
| Issue: | 8 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2024-08-12 |
| Start Page: | 1336 |
| End Page: | 1351.e9 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2024.06.006 |
| PUBMED: | 39029462 |
| PROVIDER: | scopus |
| PMCID: | PMC12147762 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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