Alex van Vliet

Extended data on Figure 6: Low expression of ELOB/C is associated with dedifferentiation in human melanomas.

Extended data on Figure 1: Whole genome-wide CRISPR-Cas9 screenidentifies several negative regulators of AXL.

Extended data on Figure 3: Elongin B/C regulate AXL independently of hypoxia.

Modulation of AXL neither affects cell proliferation nor sensitivity to MEK inhibition.

Extended data on Figure 2: Elongin BC complex members serve as keyAXL regulators.

Extended data on Figure 5: Low expression of ELOB/C is associated with phenotype switching and EMT.

Supplementary Figure Legends 1-7

Extended data on Figure 4: Elongin B/C interact with AXL and loss of Elongin B/C stabilizes AXL protein levels.

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.

Modulation of AXL neither affects cell proliferation nor sensitivity to MEK inhibition.