Publication date: Jul 04, 2025
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 cellular apoptosis and that re-expression of CDS1 rescues this cell fitness defect. We extend our analysis using pan-cancer data, confirming increased CDS2 essentiality in diverse tumor types with low CDS1 expression. Thus, the CDS1/CDS2 axis is a therapeutic target across a range of cancers.
| Concepts | Keywords |
|---|---|
| Cancer | Cds1 |
| Crispr | Cds2 |
| Diacylglycerol | Crispr |
| Knockout | Diacylglycerol |
| Libraries | Expression |
| Gene | |
| Interaction | |
| Lethal | |
| Low | |
| Melanoma | |
| Synthase | |
| Synthetic | |
| Therapeutic | |
| Tumor | |
| Uveal |
Semantics
| Type | Source | Name |
|---|---|---|
| disease | MESH | uveal melanoma |
| disease | MESH | tumor |
| drug | DRUGBANK | Pentaerythritol tetranitrate |
| pathway | REACTOME | Apoptosis |