Figure 4 from DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition

Abstract

<p>Integrated gene and protein expression profiling of trametinib-resistant DIPG cells. <b>A,</b> Coordinately downregulated genes (left), proteins (middle), and phospho-sites (right) in all three trametinib-resistant subclones of ICR-B169 <i>BRAF</i><sup>G469V</sup> cells as compared with parental. <b>B,</b> Coordinately upregulated genes (left), proteins (middle), and phospho-sites (right) in all three trametinib-resistant subclones, as compared with ICR-B169 parental (gray). T1, <i>MEK2</i><sup>I115N</sup>, pink; T3, <i>MEK1</i><sup>I141S</sup>, purple; T6, <i>MEK1</i><sup>K57N</sup>, red. <b>C,</b> GSEA enrichment plots for the signature VERHAAK_GLIOBLASTOMA_PRONEURAL in T6 <i>MEK1</i><sup>K57N</sup> cells compared with ICR-B169 parental. The curves show the enrichment score on the <i>y</i>-axis and the rank list metric on the <i>x</i>-axis. Alongside is a heat map representation of expression of significantly differentially expressed genes in the signature in all three trametinib-resistant clones compared with parental. <b>D,</b> GSEA enrichment plots for the signature HALLMARK_EPITHELIAL_MESENCHYMAL_ TRANSITION in T6 <i>MEK1</i><sup>K57N</sup> cells compared with ICR-B169 parental. The curves show the enrichment score on the <i>y</i>-axis and the rank list metric on the <i>x</i>-axis. Alongside is a heat map representation of expression of significantly differentially expressed genes in the signature in all three trametinib-resistant clones compared with parental. <b>E,</b> GSEA enrichment plots for the signature HUANG_DASATINIB_RESISTANCE_UP in T6 <i>MEK1</i><sup>K57N</sup> cells compared with ICR-B169 parental. The curves show the enrichment score on the <i>y</i>-axis and the rank list metric on the <i>x</i>-axis. Alongside is a heat map representation of expression of significantly differentially expressed genes in the signature in all three trametinib-resistant clones compared with parental. T1, <i>MEK2</i><sup>I115N</sup>, pink; T3, <i>MEK1</i><sup>I141S</sup>, purple; T6, <i>MEK1</i><sup>K57N</sup>, red.</p>

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