Fig. 1: Mesenchymal neuroblastomas are specifically vulnerable to MEK inhibitors.

A Heatmap of z-score of quantile-ranked drug sensitivity scores (DSSasym) based on metabolic activity for all 24 tested neuroblastoma cell lines to the drug library of 75 drugs. Cells were cultured as 3D spheroids and treated for 72 h. Mesenchymal-adrenergic score and molecular alterations for all neuroblastoma cell lines are indicated in the top annotation. B Pearson’s correlation between mes/adr score and mean DSSasym of 24 neuroblastoma cell lines. Correlations were calculated for all drugs, apoptotic modulators, kinase inhibitors, differentiating agents and conventional (con.) chemotherapeutics. Dots represent cell lines and are colored according to the mesenchymal-adrenergic gene signature score. C Principal component analysis (PCA) performed on DSSasym of 24 neuroblastoma cell lines. Dots represent cell lines and are colored according to the mesenchymal-adrenergic gene signature score (see (B)). D PCA Biplot, loading arrows represent the weight each drug response has on PC1 and PC2. E Pearson’s correlation between mes/adr score and mean DSSasym of 24 neuroblastoma cell lines for MEK inhibitors. Dots represent cell lines and are colored according to the mesenchymal-adrenergic gene signature score (see (B)). Crossbars represent geometric means, and the classes were compared using the Wilcox rank sum test. F Scatter plot showing correlation between MAPK inhibitor sensitivity (MSS) and MAPK activity (MPAS) and mesenchymal-adrenergic score of a gene expression data set of 39 neuroblastoma cell lines. Venn diagrams display hardly any overlap between the gene signatures. G Example images of tumor spheroids of six neuroblastoma cell lines (n = 3 adrenergic and n = 3 mesenchymal) treated with increasing concentrations of trametinib for 72 h. Viable cells are stained with the mitochondrial membrane potential indicator TMRE (yellow) and dead cells with reddot (red), scale bar 250 µm.