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. 2019 Jul 8;5:20. doi: 10.1038/s41540-019-0098-z

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 2 — Identification of synergistic and antagonistic target interactions behind drug combinations. a Opposite drug combination effects for midostaurin–nilotinib (left panel) versus midostaurin–motesanib (right panel). Motesanib alone produced a minimal effect on cell viability (black curves). In the pairwise combinations, 3 µM nilotinib or motesanib was combined with midostaurin across seven concentrations, ranging from 10 to 10,000 nM. Compared to the reference dose-response curves of no synergy (green dotted lines), nilotinib potentiated midostaurin (red curve in the left panel), while motesanib antagonized midostaurin (blue curve in the right panel). b Identification of the target interactions behind the TIMMA-predicted midostaurin–nilotinib synergy and the midostaurin–motesanib antagonism. To explain the synergistic and antagonistic interactions, the possible target combinations were determined from the kinome-wide drug-target interactions²¹ and gene expression data,²² resulting in three groups of potential target pairs: Group 1 (G1) contains the target pairs that are unique to midostaurin–nilotinib combination. Group 2 (G2) contains the target pairs that are shared between midostaurin–nilotinib and midostaurin–motesanib combinations. Group 3 (G3) contains the target pairs that are unique to midostaurin–motesanib combination. A kinase was defined as target for a given drug if the dissociation constant (K_d) is lower than 10-fold of the minimal K_d across all the kinases for this drug. Further, non-expressed targets were removed if their log2 gene expression values were lower than 6 in MDA-MB-231 cells, according to the mRNA expression data from the Cancer Cell Line Encyclopedia.²² All the target pairs were profiled in-house using the double siRNA knock-down experiments, resulting in the identification of the synergistic and antagonistic target interactions. c Left panel: the percentage inhibition and synergy scores for the target interactions in the siRNA combination experiments. AURKB–ZAK interaction (red triangle) showed top synergy among all the target pairs (p < 0.001), while the AURKB–CSF1R interaction (blue triangle) showed strong antagonistic effects (p < 0.05). Right panel: the synergy scores for the target interactions involving CSF1R and ZAK separately (p < 0.01). The green dotted line shows the baselines of zero synergy. Statistical significance was evaluated using Wilcoxon rank sum test (two-sided)