Arnoldus Tim, van Vliet Alex, Bleijerveld Onno B, de Groot Adriaan F H, Piao Qinglin, Blomberg Niek, Schatton Désirée, Dong Jing, van Hal-van Veen Susan E, Harkes Rolf, Grootemaat Anita E, Proost Natalie, Cabukusta Birol, Frezza Christian, van de Ven Marieke, van der Wel Nicole N, Giera Martin, Altelaar Maarten, Peeper Daniel S
Division of Molecular Oncology and Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Proteomics facility, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Nat Genet. 2025 Jul 4. doi: 10.1038/s41588-025-02221-2.
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.
基于癌症基因组改变的合成致死相互作用（SLIs）已在治疗方面进行了探索。我们研究了作为癌症和正常组织中差异RNA表达函数的SLI空间。对功能基因组和基因表达资源的计算分析揭示了旁系同源物胞苷二磷酸二酰基甘油合酶1（CDS1）和CDS2之间的癌症特异性SLI。对于间充质样癌症观察到CDS2对细胞存活的必要性，这些癌症CDS1表达低或无表达，约占所有癌症的一半。从机制上讲，CDS1-2 SLI伴随着脂质稳态的破坏，包括胆固醇酯和甘油三酯的积累以及细胞凋亡。在CDS1阴性癌细胞中进行的全基因组CRISPR-Cas9敲除筛选未发现由CDS2缺失引起的死亡的常见逃逸机制，表明SLI的稳健性。合成致死由CDS2剂量驱动并取决于催化活性。因此，CDS2可能作为间充质样癌症中一个药理学上易于处理的靶点。
