Figure 5 from DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition

Abstract

<p>Reciprocity of drug sensitivities and gene expression signatures between trametinib and dasatinib in DIPG cells. <b>A,</b> Dose–response curves for ulixertinib tested against ICR-B169 parental cells (gray) and resistant clones T1 (<i>MEK2</i><sup>I115N</sup>, pink), T3 (<i>MEK1</i><sup>I141S</sup>, purple), and T6 (<i>MEK1</i><sup>K57N</sup>, red). <b>B,</b> Dose-response curves for dasatinib tested against ICR-B169 parental cells (gray) and resistant clones. Concentration of compound is plotted on a log scale (<i>x</i>-axis) against cell viability (<i>y</i>-axis). Means plus standard errors are plotted from at least <i>n</i> = 3 experiments. *, <i>P</i> < 0.05; **, <i>P</i> < 0.01; ***, <i>P</i> < 0.001, AUC <i>t</i> test. <b>C,</b> Box plot of dasatinib GI<sub>50</sub> values (log scale, <i>y</i>-axis) for primary patient-derived cultures separated by trametinib sensitivity status. <b>D,</b> Box plot of trametinib GI<sub>50</sub> values (log scale, <i>y</i>-axis) for primary patient-derived cultures separated by dasatinib sensitivity status. **, <i>P</i> < 0.001, <i>t</i> test. <b>E,</b> GSEA enrichment plots for the signature VERHAAK_GLIOBLASTOMA_PRONEURAL in primary patient-derived cultures separated by trametinib (top) or dasatinib (bottom) sensitivity status. The curves show the enrichment score on the <i>y</i>-axis and the rank list metric on the <i>x</i>-axis. Alongside are heat map representations of expression of significantly differentially expressed genes in the signature in all trametinib- or dasatinib-resistant versus sensitive cell cultures. <b>F,</b> GSEA enrichment plots for the signature HALLMARK_EPITHELIAL_ MESENCHYMAL_TRANSITION in primary patient-derived cultures separated by trametinib (top) or dasatinib (bottom) sensitivity status. The curves show the enrichment score on the <i>y</i>-axis and the rank list metric on the <i>x</i>-axis. Alongside are heat map representations of expression of significantly differentially expressed genes in the signature in all trametinib- or dasatinib-resistant versus sensitive cell cultures. <b>G,</b> GSEA enrichment plots for the signature HUANG_DASATINIB_RESISTANCE_UP in primary patient-derived cultures separated by trametinib (top) or dasatinib (bottom) sensitivity status. The curves show the enrichment score on the <i>y</i>-axis and the rank list metric on the <i>x</i>-axis. Alongside are heat map representations of expression of significantly differentially expressed genes in the signature in all trametinib- or dasatinib-resistant versus sensitive cell cultures.</p>

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