Abstract 397: SMARCA4 is a selective vulnerability in SMARCA2-deficient esophageal squamous cell carcinoma cell lines

Esophageal squamous cell carcinoma (ESCC) is a highly prevalent tumor type with poor prognosis and limited treatment options. In this study, we aimed to discover potential novel drug targets using a pooled epigenome sgRNA viability screen in a panel of ESCC cell models. We identify the BAF chromatin remodeling helicase subunit SMARCA4/BRG1 as a novel dependency in a subset of ESCC cell lines. In line with the established synthetic lethal interaction of SMARCA4 and SMARCA2/BRM, the two mutual exclusive catalytic subunits of the BAF complex, SMARCA4-dependent cell lines display low or absent expression of SMARCA2. In rescue studies using SMARCA4 variants, we demonstrate that SMARCA4-dependency is linked to its ATPase/helicase activity, but not to bromodomain function. Similarly, ectopic expression of wild-type and bromodomain-mutant SMARCA2, but not a helicase-dead variant, rescues from loss of SMARCA4 in SMARCA2-low ESCC cells. SMARCA2-proficient ESCC cell models are rendered SMARCA4-dependent upon CRISPR/Cas9-mediated knock-out of SMARCA2. We further identify SMARCA4-dependent cell models from additional tumor types (colon, ovarian and pancreas carcinoma) with low or absent SMARCA2 expression. These findings expand the concept of SMARCA2/SMARCA4 paralog dependency and indicate pharmacological inhibition of SMARCA4 as a novel opportunity for targeted therapy of SMARCA2-deficient cancers. Citation Format: Katharina Ehrenhöfer-Wölfer, Teresa Puchner, Silvia Blaha-Ostermann, Alexandra Hörmann, Wolfgang Sommergruber, Norbert Schweifer, Thomas Zichner, Andreas Schlattl, Ralph A. Neumüller, Manfred Koegl, Mark P. Petronczki, Mark Pearson, Simon Wöhrle. SMARCA4 is a selective vulnerability in SMARCA2-deficient esophageal squamous cell carcinoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 397.