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

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

PROVIDER: PRJNA991607 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25155468_1.fastq.gz	Fastqsanger.gz
	SRR25155468_2.fastq.gz	Fastqsanger.gz
	SRR25155469_1.fastq.gz	Fastqsanger.gz
	SRR25155469_2.fastq.gz	Fastqsanger.gz
	SRR25155470_1.fastq.gz	Fastqsanger.gz

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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 [RNA-Seq]

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

| PRJNA991608 | ENA

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

Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers

Project description:The mammalian SWI/SNF helicase SMARCA4 is frequently mutated in cancer and inactivation results in a cellular dependence on its paralog, SMARCA2, thus making SMARCA2 an attractive synthetic lethal target. However, published data indicates that achieving a high degree of SMARCA2 selectivity is likely essential to afford an acceptable therapeutic index and this has been a considerable challenge due to the homology between paralogs. Herein we report the discovery of the first potent and selective SMARCA2 proteolysis-targeting chimera (PROTAC) molecule. Selective degradation was achieved in the absence of selective PROTAC binding and translated to potent in vitro growth inhibition and in vivo efficacy in SMARCA4 mutant models, compared to wild type models. Global ubiquitin mapping and proteome profiling revealed no unexpected off-target degradation. Our study thus highlights the ability to transform a non-selective SMARCA2-binding ligand into a selective and efficacious in vivo SMARCA2 PROTAC, providing a potential therapeutic opportunity for SMARCA4 mutant patients.

2022-09-22 | PXD036865 | Pride

Chromatin accessibility of lung cancer cells reconstituted with SMARCA4 WT or SMARCA4 mutants with and without SMARCA2 depletion

Project description:Using ATAC-seq, we identified the accessibility changes in lung cancer cells (NCI-H1944) reconstituted with SMARCA4 WT or SMARCA4 mutants. We also determined the SMARCA2-regulated accessibility program in NCI-H1944 after SMARCA2 depletion. Lastly, we identified the SMARCA2 accessibility program that is rescued by SMARCA4 WT and mutants. The "SAMPLE_ID" sample characteristic is a sample identifier internal to Genentech.

2020-09-10 | GSE144840 | GEO

Selective PROTAC-mediated degradation and shRNA-driven knockdown of SMARCA2 in HCC2302 lung adenocarcinoma cells

Project description:SMARCA2 and SMARCA4 are mutually-exclusive, core catalytic subunits for the chromatin remodeling SWI/SNF complex. Mutations in SMARCA4 are common in lung adenocarcinoma and have shown synthetic lethality with loss of SMARCA2 loss of function. The purpose of this project is to answer questions related to the in vivo [mouse xenograft] efficacy of A947, a SMARCA2 degrader. The study involves in vitro versus in vivo comparisons of drug activity, in addition to genetic manipulation of the target. Model system: HCC2302 (RRID:CVCL_V636); Model origin: Lung Adenocarcinoma; Perturbation: A947 (VHL-PROTAC-based degrader)

2022-06-13 | GSE205542 | GEO

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