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Series GSE249362 Query DataSets for GSE249362
Status Public on Jun 14, 2024
Title Non-Canonical BAF and mSWI/SNF Regulates POU2F3 and are Selective Targetable Dependencies for POU2F3-Positive Small Cell Lung Cancer
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary ~12% of SCLCs are marked by the lineage transcription factor POU2F3, which is essential in all POU2F3-positive SCLCs. Thus, approaches to directly or indirectly inhibit POU2F3 could lead to new therapeutic strategies for POU2F3-positive SCLCs. Here we use a positive selection screening strategy where endogenous POU2F3 is fused to the suicide gene DCK*. Cells that express endogenous POU2F3-DCK* are killed in the presence of the nucleoside analog BVdU and only cells that downregulate the POU2F3-DCK* fusion survive. Genome-wide CRISPR/Cas9 resistance screens with BVdU in POU2F3-DCK* cells uncovered that inactivation of SMARCD1 or BRD9, both components of the non-canonical BAF (ncBAF) complex, markedly downregulate endogenous POU2F3. We find that all POU2F3-positive SCLC cell lines relative to ASCL1-positive and NEUROD1-positive cell lines, are exquisitely sensitive to mSWI/SNF complex inhibition using SMARCA2/4 inhibitors; while pure non-neuroendocrine POU2F3-positive SCLC cell lines are highly sensitive to ncBAF complex inhibition using highly selective BRD9 degraders. Mechanistically, BRD9 binds and regulates POU2F3 target genes including POU2F3 itself. BRD9 degraders or SMARCA2/4 inhibitors robustly decrease accessibility of POU2F3 target genes effectively shutting off POU2F3 function. Moreover, BRD9 degraders or SMARCA2/4 inhibitors decrease tumor growth and increase survival of mice bearing non-neuroendocrine POU2F3 xenografts. This works shows that mSWI/SNF and ncBAF tightly regulate POU2F3 expression and activity and nominate mSWI/SNF or ncBAF inhibition as druggable therapeutic strategies to selectively target POU2F3-positive SCLCs.
 
Overall design To investigate the relationship between POU2F3 and mSWI/SNF activity in POU2F3+ small cell lung cancer (SCLC), we assess the gene expression and chromatin accessibility effects across 4 POU2F3+ SCLC lines treated with FHD286, which is a selective SMARCA2/4 inhibitor. We performed RNA-seq and ATAC-seq on NCIH211, CORL311, NCIH526, and NCIH1048 treated with either DMSO or 100nM FHD286 for 72 hours.

To understand how non-neuroendocrine POU2F3+ SCLC are sensitive to ncBAF activity, we assessed the gene expression and chromatin accessibility effects on NCIH211 and NCIH1048 treated with either DMSO or FHD609, which is a specific bromodomain-targeting PROTAC for BRD9. We performed RNA-seq and ATAC-seq on NCIH211 and NCIH1048 treated with either DMSO or 100nM FHD609 for 72 hours.

We assessed how POU2F3 binding is affected by SMARCA2/4 inhibition or BRD9 degradation. We performed POU2F3, RPB1, H3K27ac, and BRD9 ChIP-seq in NCIH1048 treated with DMSO or FHD286. We also performed POU2F3 and H3K27ac ChIP-seq in NICH1048 treated with FHD609.
 
Contributor(s) So K, Ying AW, Kadoch C
Citation(s) 39029464
Submission date Dec 05, 2023
Last update date Jul 23, 2024
Contact name Cigall Kadoch
E-mail(s) Cigall_Kadoch@dfci.harvard.edu
Organization name Dana Farber Cancer Institute
Department Pediatric Oncology
Lab Kadoch Lab
Street address 440 Brookline Ave
City Boston
State/province Massachusetts
ZIP/Postal code 02215
Country USA
 
Platforms (2)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (125)
GSM7937497 20230718_KS127_ChIP_NCIH1048_DMSO_RPB1_DX2_rep1
GSM7937498 20230718_KS128_ChIP_NCIH1048_DMSO_H3K27ac_DX2_rep1
GSM7937499 20230718_KS129_ChIP_NCIH1048_DMSO_BRD9_DX2_rep1
Relations
BioProject PRJNA1048875

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Supplementary file Size Download File type/resource
GSE249362_RAW.tar 9.4 Gb (http)(custom) TAR (of BED, BW, TAB)
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Raw data are available in SRA
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