Fig. 4: Inhibiting de-differentiation increases the efficacy of BRAFi.

a Each point is the relative area under the curve (AUC) of the BRAFi dose-response curve in combination with drugs targeting the proteins indicated in the panel headers for a given cell line. The dotted line indicates no difference compared to BRAFi alone. Colors indicate whether a cell line belongs to the de-differentiated or differentiated class. Eight concentrations of VEM, up to 5 uM, were used to generate the dose-response curves. For the drug combinations, a constant dose of 1 uM Saracatinib, 1 uM JNK-IN-8, 1 uM of MK2206, or 4 uM of Fasudil was added to varying concentrations of VEM. The edges of the boxes in this plot denote the 1st and 3rd quartiles, and the line indicates the 2nd quartile. b Same dataset visualized in a shown for each cell line. The y-axis, which presents the area under the curve, represents the entire area under the dose-response curve shown in Supplementary Fig. 6. The lower the area, the more sensitive a cell line is to the respective drug. As detailed in the methods, each dose was measured in triplicates. The area is one value, so no statistics can be performed. c Enrichment plots of RAC1-responsive gene set and Tsoi undifferentiated gene set in genes differentially expressed upon SRCi. d Venn diagram of the number of differentially expressed genes shared or not upon RAC1-knockdown or SRCi.