Abstract
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.
Highlights
Cancer-relevant paralog dependencies are prominently observed for BRG1-Associated Factor (BAF) chromatin remodeling complexes[13]
Stable Cas9-expressing cell lines were transduced with a single guide RNA (sgRNA) library consisting of >1300 sgRNAs targeting 179 epigenetic regulators[38] and negative selection of sgRNA-expressing cells was monitored by next-generation sequencing after 18 population doublings (Fig. 1A)
While recent large scale genomic analyses have provided a detailed landscape of genomic alterations in ESCC33–36, approaches to clinically exploit selective vulnerabilities in Esophageal squamous cell carcinoma (ESCC) with targeted agents have proven unsuccessful to date[45,47,48]
Summary
Cancer-relevant paralog dependencies are prominently observed for BRG1-Associated Factor (BAF) chromatin remodeling complexes[13]. Cancer-associated BAF alterations do not result in complete abrogation of BAF activity, which would be detrimental for viability of most cells, implying that tumors are dependent on the aberrant function of the residual BAF complex[13]. This is exemplified by the ATPase subunit SMARCA4, which is frequently inactivated by loss-of-function mutations or epigenetic silencing in non-small cell lung cancer (NSCLC) and other tumor types[21,22,23,24]. This concept is further extended to non-ESCC cancer cell models, indicating SMARCA4 as a potential therapeutic target in tumors with low or absent expression of SMARCA2
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
