Fig. 6: INKA prediction of active kinases identifies synergistic combinations in patient-derived xenografts. | Nature Communications

Fig. 6: INKA prediction of active kinases identifies synergistic combinations in patient-derived xenografts.

From: Phosphoproteomic profiling of T cell acute lymphoblastic leukemia reveals targetable kinases and combination treatment strategies

Fig. 6

a PDXs were obtained from T-ALL primary cells expanded in NSG mice. Purified human blasts were used for phosphoproteomics, INKA analyses, and ex vivo drug screening using a 10-by-10 drug concentrations matrix. b Top20 INKA kinases from the phosphotyrosine (pY) dataset. Each bar plot illustrates the highest 20 active kinases in four PDXs ranked on their INKA score. Orange, INSR/IGF-1R; gray, JAKs; c Dose-response curves of dasatinib and BMS-754807 in T-ALL PDX cells (T-ALL PDX-01 to 04). Cells were treated for 72 h with increasing concentrations of either dasatinib or BMS-754807 (1 nM–10 µM range) and viability was calculated in relation to untreated control cells (DMSO only). Each point represents the mean and standard deviation of the duplicate. d Zero-Interaction Potency (ZIP) synergy scores for the combination of dasatinib and BMS-754807 in a 1 nM–10 µM concentration range. Cells were treated with either one of the single drugs or a drug combination for 72 h in duplicate. Cell survival was calculated in comparison to untreated cells (DMSO only). ZIP values lower than 0 indicate an antagonistic effect of the drug combination (blue), values between 0 and 10 indicate an additive effect (white to light red) while values above 10 (corresponding to a deviation from the reference model above 10%) indicate synergy (dark red and outside black dashed line). Each drug screening was performed in duplicate. e Dose-response curves of dasatinib and ruxolitinib in T-ALL PDX cells. Cells were treated for 72 h with increasing concentrations of either dasatinib or ruxolitinib (1 nM–10 µM range) and viability was calculated in relation to untreated control cells (DMSO only). Each point represents the mean and standard deviation of the duplicate. f ZIP synergy scores for the combination of dasatinib and ruxolitinib in a 1 nM–10 µM concentration range. Cells were treated with either one of the single drugs or a drug combination for 72 h in duplicate. Relative viability vas calculated in comparison to untreated cells (DMSO only). Each drug screening was performed in duplicate. Source data are provided as a Source Data file.

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