Cytidine diphosphate diacylglycerol synthase 2 is a synthetic lethal target in mesenchymal-like cancers.

ABSTRACT: Synthetic lethal interactions (SLIs) based on genomic alterations in cancer have been therapeutically explored. We investigated the SLI space as a function of differential RNA expression in cancer and normal tissue. Computational analyses of functional genomic and gene expression resources uncovered a cancer-specific SLI between the paralogs cytidine diphosphate diacylglycerol synthase 1 (CDS1) and CDS2. The essentiality of CDS2 for cell survival is observed for mesenchymal-like cancers, which have low or absent CDS1 expression and account for roughly half of all cancers. Mechanistically, the CDS1-2 SLI is accompanied by disruption of lipid homeostasis, including accumulation of cholesterol esters and triglycerides, and apoptosis. Genome-wide CRISPR-Cas9 knockout screens in CDS1-negative c

SUBMITTER: Arnoldus T 

PROVIDER: S-EPMC12283369 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature