Fig. 8

Antitumoral effects of MEK inhibition are significantly enhanced by the combination with disulfiram in a BRAF WT melanoma xenograft model. A Sketch of the mouse experiment with four different therapy arms using the BRAF WT PDX melanoma model TÜMEL173. The four different groups were treated daily with vehicle (sham), DSF (50 mg/kg), trametinib (0.3 mg/kg) or their combination for 35 days. B Tumor end (day 35) volumes for all the respective therapy groups (control, trametinib, DSF and combination therapy) are shown (control n=6, DSF n=5, trametinib n=5, combination n=6). Significance was determined by versions of one-way ANOVA (Welch and Brown-Forsythe) with subsequent Dunnett’s multiple comparisons test. C Growth curves of subcutaneous TÜMEL173 melanomas in NSG mice treated with sham (Ctrl) the MEK inhibitor trametinib (trame), DSF and combination (±SEM). D Progression-free survival of the animals during the 35 days under treatment. Progression was defined as 20% increase in the tumor volume (log-rank/Mantel-Cox test). E Confocal immunofluorescence analysis of phospho-ERK1/2 and JUN in TÜMEL173 tumors after 35 days of treatment with sham (Ctrl), trametinib (Trame), disulfiram (DSF) or the combination (red color: phospho-ERK1/2; blue color: JUN; green: nuclei /Yopro-1; scale bar 50 µm). F Fluorescence intensities of phospho-ERK1/2 and JUN staining were used for quantification (≥ 400 cells/group were analyzed). Kruskal-Wallis with subsequent Dunn’s multiple comparisons test. *p< 0.05; ** p < 0.01; *** p < 0.001; and **** p < 0.0001, ns (not significant)