Cytidine diphosphate diacylglycerol synthase 2 is a synthetic lethal target in mesenchymal-like cancers
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.
Authors
- Anita E. Grootemaat (ORCID: https://orcid.org/0000-0002-4209-8232)
- Désirée Schatton (ORCID: https://orcid.org/0009-0007-7554-8985)
- Marieke van de Ven (ORCID: https://orcid.org/0000-0001-6779-9353)
- Natalie Proost (ORCID: https://orcid.org/0009-0001-3282-793X)
- Maarten Altelaar (ORCID: https://orcid.org/0000-0001-5093-5945)
- Christian Frezza (ORCID: https://orcid.org/0000-0002-3293-7397)
- Birol Cabukusta (ORCID: https://orcid.org/0000-0002-1187-3048)
- Anne F. de Groot (ORCID: https://orcid.org/0000-0001-7612-2918)
- Martin Giera (ORCID: https://orcid.org/0000-0003-1684-1894)
- Susan E. van Hal-van Veen (ORCID: https://orcid.org/0000-0002-4196-133X)
- Nicole N. van der Wel (ORCID: https://orcid.org/0000-0001-6392-3417)
- Rolf Harkes (ORCID: https://orcid.org/0000-0001-6592-654X)
- Onno B. Bleijerveld (ORCID: https://orcid.org/0000-0002-9395-2347)
- Alex v. Vliet (ORCID: https://orcid.org/0000-0001-9399-2894)
- Daniel S. Peeper (ORCID: https://orcid.org/0000-0003-1293-3177)
- Tim Arnoldus (ORCID: https://orcid.org/0009-0005-2104-4832)
- Jing Ming Dong
- Niek Blomberg
- Qinglin Piao
Institutions
- Utrecht University (NL)
- Leiden University Medical Center (NL)
- Netherlands Metabolomics Centre (NL)
- Oncode Institute (NL)
- Cancer Genomics Centre (NL)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Amsterdam University Medical Centers (NL)
- University of Amsterdam (NL)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-07-01
- DOI
- https://doi.org/10.1038/s41588-025-02221-2
- Citations
- 3
- Primary Topic
- Lipid metabolism and biosynthesis
- Type
- article
- Field-Weighted Citation Impact
- 3.34