Fig. 6: Co-treatment of BCL-2 and the OxPhos pathway re-sensitizes VEN-resistant PDX samples.
A Twelve PDX samples were incubated with increasing concentrations of VEN (DMSO; 10 nM; 50 nM; 100 nM; 1 µM; 5 µM; 10 µM), Oligomycin (DMSO; 10 nM; 50 nM; 100 nM; 1 µM; 5 µM; 10 µM) or titrated in an one to one matrix combination and incubated for 24 h. Cell death was analyzed using flow cytometry after propidium iodide staining. Interaction landscapes of the dose-response matrix analyses are shown. To estimate synergy, δ-scores were calculated using synergyfinder. Synergistic effects are shown in red, additive effects in white and antagonistic effects in green. The Bliss synergy score shown indicates the average synergy score across the dose-response matrix. B Comparing VENsens and highly VENins PDX samples (EC50 > 1 µM). Unpaired two-tailed Student’s T-test was used to calculate p-values (± standard deviation is shown). C When VENsens samples were treated with VEN, pro-apoptotic BIM is displaced from BCL-2 to MCL-1 thereby initiating BAX/BAK pore formation, cytochrome c release and cell death induction. Conversely, when VENins samples are treated with VEN, BIM is liberated from BCL-2 but increased MCL-1/BIM binding is present. Additionally, VENins samples are characterized by increased metabolic activity, increased mtDNA content and elongated mitochondrial structures. Of note, co-treatment of VEN and OxPhos inhibitors re-sensitizes VEN-resistant cells to cell death induction. Created with BioRender.com.
