biostudies-literatureChan PYRCUK | Biotechnology and Biological Sciences Research CouncilWellcome TrustCenter for Strategic Scientific Initiatives, National Cancer InstituteBiotechnology and Biological Sciences Research CouncilCSRD VA1672-1683https://www.ebi.ac.uk/biostudies/studies/S-EPMC12283370biostudies-literatureUnknown57(7)Metastatic uveal melanoma is an aggressive disease with limited effective therapeutic options. To comprehensively map monogenic and digenic dependencies, we performed CRISPR-Cas9 screening in ten extensively profiled human uveal melanoma cell line models. Analysis involved genome-wide single-gene and combinatorial paired-gene CRISPR libraries. Among our 76 uveal melanoma-specific essential genes and 105 synthetic lethal gene pairs, we identified and validated the CDP-diacylglycerol synthase 2 gene (CDS2) as a genetic dependency in the context of low CDP-diacylglycerol synthase 1 gene (CDS1) expression. We further demonstrate that CDS1/CDS2 forms a synthetic lethal interaction in vivo and reveal that CDS2 knockout results in the disruption of phosphoinositide synthesis and increased cellulaNature geneticsThe synthetic lethal interaction between CDS1 and CDS2 is a vulnerability in uveal melanoma and across multiple tumor types.PMC122833701220540/Z/20/ABB/T002530/1BB/Y006925/1Woods MRaimondi FStephens LVinceti AThompson NAWessels LMehta IHawkins PTvan de Haar JBisceglia LAdams DJAlexander DGoncalves EHarle VKozik ZDel Castillo Velasco-Herrera MIyer VWong KPatiyal SMatsuyama LSASOlvera-Leon RVazquez-Cruz MEBalmus GArriaga-Gonzalez FGPark JSvan der Weyden LOfford VIorio FRyan CJSinha SChan PYChoudhary JVenkatesh ABarneda DCheema SfalseThe synthetic lethal interaction between CDS1 and CDS2 is a vulnerability in uveal melanoma and across multiple tumor types.Metastatic uveal melanoma is an aggressive disease with limited effective therapeutic options. To comprehensively map monogenic and digenic dependencies, we performed CRISPR-Cas9 screening in ten extensively profiled human uveal melanoma cell line models. Analysis involved genome-wide single-gene and combinatorial paired-gene CRISPR libraries. Among our 76 uveal melanoma-specific essential genes and 105 synthetic lethal gene pairs, we identified and validated the CDP-diacylglycerol synthase 2 gene (CDS2) as a genetic dependency in the context of low CDP-diacylglycerol synthase 1 gene (CDS1) expression. We further demonstrate that CDS1/CDS2 forms a synthetic lethal interaction in vivo and reveal that CDS2 knockout results in the disruption of phosphoinositide synthesis and increased cellula2025-01-01T00:00:00Z2025 Jul2026-07-15T06:53:21.162Z2025-08-16T03:06:08.835ZS-EPMC122833704061567510.1038/s41588-025-02222-1