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• W3000431430 abstract "The cohesin complex comprises four core subunits: RAD21, SMC3, SMC1A, and STAG2. Cohesin is required for many biological processes, including sister chromatid cohesion, DNA damage response, regulation of gene expression, and ribosomal biogenesis. Germline mutations of cohesin subunits or their regulators give rise to human developmental disorders, while somatic mutations in cohesin subunits are found in a wide range of human cancers, including acute myeloid leukemia (AML) (12%), Ewing sarcoma (15%) and glioblastoma (19%). In particular, cohesin subunit STAG2, has been identified as one of only 12 genes that are significantly mutated in more than 4 human cancers. Currently, there is no targeted therapeutic strategy for cancer patients with cohesin mutations. Synthetic lethality has emerged as a promising approach for targeted therapy. While synthetic lethal interactions of STAG2 have been demonstrated with its paralog, STAG1, and with the DNA damage repair pathway, synthetic lethal interactions with other pathways have not been explored. To identify synthetic lethal drug activity with cohesin mutations, we generated three isogenic cohesin-deficient MCF10A cell lines (RAD21+/-,SMC3+/-, and STAG2-/-) using CRISPR/Cas9. Cohesin-deficient MCF10A cell lines are sufficiently similar to their parental line concerning growth rate and chromosome stability. However, these cell lines exhibit alterations in nucleolar morphology and increased nuclear location of γH2AX and p53 (except in STAG2-/-). RNA-sequencing analysis of the cell lines showed that cohesin subunit mutation led to downregulation of genes involved in regulation of ribosome biogenesis and RNA processing. Furthermore, ribosomal stress mediated by Actinomycin D led to severe nucleolar fragmentation in cohesin-deficient MCF10A, but not MCF10A parental, suggesting that cohesin mutation might confer vulnerability to perturbation of ribosome biogenesis. Using MCF10A parental and isogenic cohesin-deficient MCF10A cell lines, we performed a quantitative high-throughput drug screen against 3,009 compounds of FDA-approved drugs, kinase, and epigenetic inhibitors. Several classes of inhibitors targeting mTOR signaling, Wnt signaling and chromatin modification were found to selectively inhibit the growth of cohesin-deficient MCF10A cells by 30% or more. WAY-600 (mTORC1/mTORC2 inhibitor) and I-BET-762 (Bromodomain inhibitor) were among the top hits. Mechanistic studies on how these drugs preferentially kill cohesin-deficient cells are under way. In summary, we have identified potential synthetic lethal compounds that may provide the basis for development of targeted therapies of cancers with cohesin deficiency or mutation. Citation Format: Chue Vin Chin, Jisha Antony, Amee J George, JinShu He, Kate Parson, Ross D Hannan, Julia A Horsfield. A synthetic lethal drug screen identifies exploitable vulnerabilities in cohesin-deficient cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A12. doi:10.1158/1535-7163.TARG-19-LB-A12" @default.
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• W3000431430 date "2019-12-01" @default.
• W3000431430 modified "2023-09-27" @default.
• W3000431430 title "Abstract LB-A12: A synthetic lethal drug screen identifies exploitable vulnerabilities in cohesin-deficient cells" @default.
• W3000431430 doi "https://doi.org/10.1158/1535-7163.targ-19-lb-a12" @default.
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