Fig. 6: Oxaliplatin-resistant HCT116 cells exhibit increased sensitivity to inhibitors of cholesterol biosynthesis and oxidative stress pathways.

A Workflow for synthetic lethal drug screen. Cells were seeded and incubated before drugs from the anti-cancer and kinase inhibitor libraries were added to the plate for a 72-h treatment. Cell viability was then determined by adding Cell-Titer Glo, and luminescence intensity was determined using a plate reader for further data analysis. B Heatmap of drug inhibition on cell viability relative to DMSO control of HCT116 oxaliplatin-resistant models using a library of FDA-approved anti-cancer and kinase inhibitor libraries (left panel). Red indicates a 100% inhibition of cell viability, while blue indicates no inhibition of cell viability compared to DMSO control. Drugs that displayed differential sensitivity between HCT116-PAR and oxaliplatin-resistant models are boxed in green along with inhibition fold change relative to HCT116-PAR (right panel). C Simvastatin IC₅₀ fold change in HCT116- LD, MD, and HD relative to PAR. D Schematic depicting in vivo treatment of simvastatin in mice harboring xenografts of HCT116-PAR, LD, MD, and HD. Tumor growth curves of simvastatin-treated HCT116 PAR (E), LD (F), MD (G), and HD (H) relative to drug vehicle treatment. Statistical significance for D–G was determined using Ordinary one-way ANOVA followed by Dunnett’s multiple comparisons test. Figure 6A, D were created with BioRender.com.