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. 2023 Jun 13;5(1):vdad073. doi: 10.1093/noajnl/vdad073

Figure 3.

Figure 3.

Model-based clustering of z-scale-normalized synergy and viability shows that 18 out of 43 drug combinations show a consistent drug interaction over 25 GBM cultures. (A) Schematic overview of assay set-up showing that on day 0, cells were seeded in a 384-well plate, and after 24 h, each drug combination was added via consecutive titration into a 6 × 6 matrix. On day 4, a CellTiter-Glo 3D readout was performed and cell viability results were analyzed via Combenefit. (B) Dimension reduction plot of synergy and viability results (z-scores) showing 3 clusters present in 43 drug combinations based on model-based clustering, that is, cluster 1 (blue, n = 11, additive with limited viability loss), cluster 2 (red, n = 18, synergy with viability loss), and cluster 3 (yellow, n = 14, additive with viability loss). (C) Mixed Scatter and Box and Whisker plot showing the raw median Loewe additivity (on the y-axis) for each cluster, showing a higher Loewe additivity in Cluster 2 compared to Cluster 3 and 1. (D) Scatterplot combined with a Box and Whisker plot showing a strong effect on minimum viability (on the y-axis) in clusters 2 and 3 compared to cluster 1. (E) Heatmap including raw synergy scores via Loewe additivity model, Highest single agent model, Bliss independence model, and the effect on minimum viability of 43 drug combinations on 25 GBM cultures ordered via the clusters retrieved via Z-score Model-based clustering. The heatmap shows a high synergy score for the 18 drug combinations included in cluster 2 (red). A high raw sum synergy score or strong effect on viability is shown in red, and antagonism or no effect on viability is shown in blue (see legend for numerical range for each synergy model). Data are average raw synergy scores (sum of synergy and antagonism) or Z-scores of 2 technical replicates. See Supplementary Table 8 for raw synergy values, see data availability for source data. Data in scatterplot/Box and Whisker plot are raw median synergy scores (n = 2) per drug combination (n = 43) of 25 GBM cultures ± Whiskers Tukey.