Fig. 3

Functionally-instructed combination therapies in vitro. a, Schematic workflow of the functionally-instructed drug screen. For all selected drugs IC₅₀ values were determined. Then, a pre-selection screen, i.e. 1 × 1 (IC₅₀xIC₅₀) combination of AZD6738 plus drug of interest, was set-up. All combinations with AZD6738 resulting in higher efficacy than additive interaction were then included in 4 × 4 synergy map analyses. b, Analysis of the 1 × 1 pre-selection screen (n = 1 with 8 technical replicates per sample). The heatmap depicts the delta value between prediction of additive drug-drug interaction and measured viability (Bliss synergy score). Positive values (blue) indicate a higher efficacy of the drug combination than predicted, negative values (red) indicate a lower efficacy of the drug combination than predicted. Tideglusib, harmine, everolimus, hydroxyurea, olaparib, temozolomide, vorinostat, cisplatin, etoposide and fludarabine phosphate were selected as top candidates. c, Analysis of the 4 × 4 synergy map experiments. Heatmap depicts the average ZIP synergy score across tested combinations (n = 2). Green coloring indicates high synergism scores, brown coloring negative synergism scores. Hydroxyurea, cisplatin and fludarabine phosphate show positive synergism values across all four cell lines tested