EP005/#572 Exploiting SMARCA2 dependency for targeted therapy in SMARCA4-deficient ovarian cancers. (4th December 2022)

• Record Type: Journal Article
• Authors: Brodeur, Melica; Dopeso, Higinio; Green, Hunter; Ito, Koichi; Hulse, Michael; Brown, Justin; Weigelt, Britta; Zamarin, Dmitriy
• Is Part Of: International journal of gynecological cancer. Volume 32(2022)Supplement 3
• Page Start: A49
• Page End: A50
• Publication Date: 2022-12-04
• Subjects: Generative organs, Female -- Cancer -- Periodicals; 616.99465
• DOI: 10.1136/ijgc-2022-igcs.96
• Languages: English
• ISSNs: 1048-891X

Abstract

Abstract : Objectives: Most ovarian cancer (OC) patients recur after first-line treatment and develop chemoresistance, highlighting an unmet need for precision medicine in OC. Half of OCs harbor mSWI/SNF chromatin-remodeling complex alterations including 10% in the SMARCA4 gene. Studies to date have suggested that the catalytic subunits of the mSWI/SNF complex, SMARCA2 and SMARCA4, exhibit paralog dependency and thus present an opportunity for synthetically lethal molecular targeting. The aim of this study is to investigate SMARCA2-dependency in SMARCA4-deficient OCs and to identify synthetic lethal interactions of SMARCA2-protein degradation in these cancers. Methods: Using CRISPR-Cas9 lentiviral-transduction targeting the SMARCA4 gene, we developed novel murine syngeneic/isogenic OC cell lines from well-characterized cell lines ID8 and UPK10, and novel electroporation-based genetically engineered mouse model-derived cell line 3_1. Human isogenic OC cell lines OAW28 were also derived using the same technique. SMARCA2 protein degrader (proteolysis-targeting chimera) was provided in collaboration with industry. Western blots were performed to define paralog dependency in SMARCA4-deficient cells and to assess adequate SMARCA2-degradation. SMARCA2 protein degrader response was assessed using viability assays. Results: SMARCA4-deficient isogenic OC cell lines displays increased SMARCA2 protein expression compared to SMARCA4-wildtype cells, suggesting that paralog dependency exists in OC. Furthermore, near complete SMARCA2-degradation occurs at low nanomolar range after 6-hour incubation. Comparing IC50 values, we show a 5-fold increased sensitivity to the SMARCA2 protein degrader in SMARCA4-deficient OC cell lines compared to control, suggesting a synthetic lethal interaction in these cancers. Conclusions: This study identifies SMARCA2 protein degradation as a unique therapeutic vulnerability and potential therapeutic target for SMARCA4-deficient OCs.