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

Authors

Tim Arnoldus, Alex van Vliet, Onno B Bleijerveld, Adriaan F H de Groot, Qinglin Piao, Niek Blomberg, Désirée Schatton, Jing Dong, Susan E van Hal-van Veen, Rolf Harkes, Anita E Grootemaat, Natalie Proost, Birol Cabukusta, Christian Frezza, Marieke van de Ven, Nicole N van der Wel, Martin Giera, Maarten Altelaar, Daniel S Peeper

Published in

Nature genetics. Jul 04, 2025. Epub Jul 04, 2025.

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 cancer cells identify no common escape mechanism of death caused by CDS2 ablation, indicating the robustness of the SLI. Synthetic lethality is driven by CDS2 dosage and depends on catalytic activity. Thus, CDS2 may serve as a pharmacologically tractable target in mesenchymal-like cancers.

PMID:
40615674
Bibliographic data and abstract were imported from PubMed on 05 Jul 2025.

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