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Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer [RNA-Seq]

ABSTRACT: Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer [RNA-Seq]

PROVIDER: PRJNA991608 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25152114_1.fastq.gz	Fastqsanger.gz
	SRR25152114_2.fastq.gz	Fastqsanger.gz
	SRR25152115_1.fastq.gz	Fastqsanger.gz
	SRR25152115_2.fastq.gz	Fastqsanger.gz
	SRR25152116_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer

Project description:Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer

| PRJNA991602 | ENA

Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer [RNA-Seq]

Project description:Lung cancer is the top cause of cancer mortality. Despite recent advances, the majority of patients with lung cancer still lack effective therapeutic options, underscoring the dire need for additional treatment approaches. Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. Recent reports have identified the paralogue SMARCA2 to be synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. To overcome this hurdle, we have utilized iterative structure-activity relationship (SAR) studies to develop novel, potent and selective SMARCA2 degrading small molecules based on proteolysis targeting chimera (PROTAC) technology. We demonstrated that YD23, our lead SMARCA2 PROTAC, potently and selectively induces degradation of SMARCA2. Mechanistically, we show that SMARCA2 degradation in SMARCA4-mutant cells induces a profound reprograming of the enhancer landscape with marked loss of chromatin accessibility at enhancers of genes involved in cell proliferation. Furthermore, we identified nuclear effectors of the Hippo pathway, YAP/TEAD, as key co-conspirators of SMARCA2 in driving the growth of SMARCA4-mutant cancer cells that can be disrupted by our degrader. Finally, we show that YD23 has a potent tumor growth inhibitory activity in SMARCA4-mutant xenograft tumors. These findings provide the mechanistic basis for development of SMARCA2 degraders as synthetic lethal therapeutics against SMARCA4 mutant tumors.

2024-09-27 | GSE236587 | GEO

Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer [ChIP-Seq]

2024-09-27 | GSE236589 | GEO

Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer [ATAC-Seq]

2024-09-27 | GSE236588 | GEO

Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer [ChIP-Seq]

Project description:Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer [ChIP-Seq]

| PRJNA991605 | ENA

Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer [ATAC-Seq]

Project description:Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer [ATAC-Seq]

| PRJNA991607 | ENA

RNA-seq analysis of NCI-H1693 cells treated with the selective SMARCA2 degrader PRT3789

Project description:The goal of this study was to examine the transcriptional consequences of selective SMARCA2 degradation in a SMARCA4-deficient non-small cell lung cancer (NSCLC) model. NCI-H1693 cells were treated with the SMARCA2 degrader PRT3789 (50 nM) or vehicle control for 6 h, 48 h, and 72 h. RNA-seq was performed to identify changes in gene expression that could reveal pathways associated with synthetic lethality and clarify the mechanism of action of SMARCA2 degraders in the absence of SMARCA4.

2025-09-12 | GSE307424 | GEO

ATAC-seq analysis of NCI-H1693 cells treated with the selective SMARCA2 degrader PRT3789

Project description:The goal of this study was to characterize genome-wide chromatin accessibility changes induced by SMARCA2 degradation in a SMARCA4-deficient non-small cell lung cancer model. NCI-H1693 cells were treated with the selective SMARCA2 degrader PRT3789 (50 nM) or vehicle control (DMSO) for 48 h. ATAC-seq was performed to identify regions of differential accessibility that may help explain the mechanism of synthetic lethality in SMARCA4-deficient contexts.

2025-09-12 | GSE307426 | GEO

Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer.

Project description: Not available

| S-EPMC11663135 | biostudies-literature

Genome binding of SMARCA2 and SMARCA4 in lung cancer cells reconstituted with SMARCA4 WT with and without SMARCA2 depletion

Project description:Using ChIP-seq, we identified the genome-wide occupancy of SMARCA2 and SMARCA4 in lung cancer cells (NCI-H1944) reconstituted with SMARCA4 WT. We also determined how SMARCA4 occupancy changed in NCI-H1944 after SMARCA2 depletion.

2020-09-10 | GSE147201 | GEO

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