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

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

PROVIDER: PRJNA613396 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11349407.fastq.gz	Fastqsanger.gz
	SRR11349408.fastq.gz	Fastqsanger.gz
	SRR11349409.fastq.gz	Fastqsanger.gz
	SRR11349410.fastq.gz	Fastqsanger.gz
	SRR11349411.fastq.gz	Fastqsanger.gz

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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.

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

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

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Expression profiling of lung cancer cells reconstituted with SMARCA4 WT and mutant K785R after SMARCA2 knockdown

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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.

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