SMARCA2-deficiency confers sensitivity to targeted inhibition of SMARCA4 in esophageal squamous cell carcinoma cell lines

Ehrenhofer-Wolfer, K., Puchner, T., Schwarz, C., Rippka, J., Blaha-Ostermann, S., Strobl, U., Hormann, A., Bader, G., Kornigg, S., Zahn, S., Sommergruber, W., Schweifer, N., Zichner, T., Schlattl, A., Neumuller, R. A., Shi, J., Vakoc, C. R., Kogl, M., Petronczki, M., Kraut, N., Pearson, M. A., Wohrle, S. (August 2019) SMARCA2-deficiency confers sensitivity to targeted inhibition of SMARCA4 in esophageal squamous cell carcinoma cell lines. Sci Rep, 9 (1). p. 11661. ISSN 2045-2322

2019.Ehrenhofer.SMARCA2.pdf - Published Version
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DOI: 10.1038/s41598-019-48152-x


SMARCA4/BRG1 and SMARCA2/BRM, the two mutually exclusive catalytic subunits of the BAF complex, display a well-established synthetic lethal relationship in SMARCA4-deficient cancers. Using CRISPR-Cas9 screening, we identify SMARCA4 as a novel dependency in SMARCA2-deficient esophageal squamous cell carcinoma (ESCC) models, reciprocal to the known synthetic lethal interaction. Restoration of SMARCA2 expression alleviates the dependency on SMARCA4, while engineered loss of SMARCA2 renders ESCC models vulnerable to concomitant depletion of SMARCA4. Dependency on SMARCA4 is linked to its ATPase activity, but not to bromodomain function. We highlight the relevance of SMARCA4 as a drug target in esophageal cancer using an engineered ESCC cell model harboring a SMARCA4 allele amenable to targeted proteolysis and identify SMARCA4-dependent cell models with low or absent SMARCA2 expression from additional tumor types. These findings expand the concept of SMARCA2/SMARCA4 paralog dependency and suggest that pharmacological inhibition of SMARCA4 represents a novel therapeutic opportunity for SMARCA2-deficient cancers.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > bromodomain and extraterminal protein
Investigative techniques and equipment > CRISPR-Cas9
CSHL Authors:
Communities: CSHL labs > Vakoc lab
CSHL Cancer Center Program > Cancer Genetics and Genomics Program
Depositing User: Matthew Dunn
Date: 12 August 2019
Date Deposited: 20 Aug 2019 20:03
Last Modified: 10 Dec 2020 20:04
PMCID: PMC6691015
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