Project description: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 using genome-wide single gene/gRNA and combinatorial paired gene/paired gRNA CRISPR libraries. Within our identified uveal melanoma-specific essential genes and synthetic lethal gene pairs, we identified and validated CDS2 as a novel genetic dependency in the context of low CDS1 expression. We further demonstrate that CDS1/CDS2 is a synthetic lethal interaction in vivo and reveal that CDS2 knockout results in the disruption of phosphoinositide synthesis, cellular apoptosis, and that re-expression of CDS1 rescues the cell fitness defect provoked by CDS2 loss. We extend our analysis using pan-cancer data confirming increased CDS2 essentiality in diverse tumour types with low CDS1 expression. Our results suggest that CDS2 inhibition should be investigated as a therapeutic strategy in uveal melanoma that may extend to multiple tumour types with low CDS1 expression. The data provided in this dataset explore the effect of CDS2 loss in uveal melanoma cell lines.