Fig. 4: Synergy analysis of combination treatments.

A Schematic of a diagonal minimal sampling design, blue colored squares are the concentration combinations that were measured in the combination screen. Grey colored squares were imputed, and mean synergy scores were calculated with the ZIP model. B Synergy-sensitivity plot of metabolic activity based, reduced matrix design synergy screen for co-treatment of lysosomal drugs (artesunate, bafilomycin A1 and chloroquine) with MAPK inhibitors (selumetinib, trametinib, ulixertinib). Two mesenchymal (HD-N.33, SH-EP) and three adrenergic cell lines (IMR-32, IMR-5/75, NMB, SH-SY5Y) were treated for 72 h. C Synergy-sensitivity plot of metabolic activity based, reduced matrix design synergy screen for co-treatment of sphingolipid metabolism inhibitors (amitriptyline, fluoxetine, nortriptyline) with MAPK inhibitors (trametinib, ulixertinib). D Graphical description of the experimental design, cells were seeded and treated with the first drug directly after seeding. After 72 h, cells were treated with senolytics. Metabolic activity readout and spheroid size analysis were done after another 72 h of incubation. E Synergy-sensitivity plot of metabolic activity based, reduced matrix design synergy screen for pre-treatment with senolytic drugs (A-1210477, A-1331852, dasatinib, iBET-151, mivebresib, navitoclax, venetoclax) before MAPK inhibitor (binimetinib, cobimetinib, selumetinib, trametinib, ulixertinib) treatment.