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

Abstract

Synthetic lethal interactions (SLIs) can provide a therapeutic index, as illustrated by PARP inhibition of BRCA-deficient cancers1–4. Whereas additional SLIs based on genomic alterations in cancer have been identified5–19, we set out to explore the SLI space as a function of differential RNA expression profiles in cancer and normal tissue. By unbiased computational analyses of publicly available functional genomic and gene expression resources we uncovered a cancer-specific SLI between the paralogs cytidine diphosphate synthase 1 (CDS1) and CDS2. The essentiality of CDS2 for cell survival is observed for mesenchymal-like cancers, which express low levels of CDS1. We confirm the CDS1-2 SLI in a panel of cultured cancer cell lines and in tumor-bearing mice. Mechanistically, the CDS1-2 SLI is accompanied by disruption of lipid homeostasis including extensive accumulation of cholesterol esters and triglycerides, and induction of apoptotic cell death. Genome-wide CRISPR-Cas9 knockout screens in a panel of CDS1-negative cancer cell lines failed to identify a common escape mechanism of death caused by CDS2 ablation, indicating the robustness of the SLI. Our findings reveal that CDS2 may serve as a pharmacologically tractable target in mesenchymal cancers, meriting therapeutic exploration.