Fig. 1: Mechanism of action of TEAD inhibitor, GNE-7883, upon short term treatment (48 h). | Nature Communications

Fig. 1: Mechanism of action of TEAD inhibitor, GNE-7883, upon short term treatment (48 h).

From: Cooperation between the Hippo and MAPK pathway activation drives acquired resistance to TEAD inhibition

Fig. 1

A Chemical structure of GNE-7883. B GNE-7883 viability dose response curve (mean ± SD) for H226 cells. Statistical significance was assessed using two-way ANOVA followed by posthoc Tukey’s multiple comparison test. (n = 12 independent treatments per condition). C Experimental schematic for acute exposure of 1 µM GNE-7883. Created with BioRender.com/v03h840. D Heatmap showing downregulation of proliferation gene signature in GNE-7883 treated cells vs DMSO control from bulk RNA-seq expression data. Color density indicates z-normalized RPKMs (reads per kilobase of transcript per million reads mapped). E Gene Set Enrichment Analysis (GSEA) of differentially expressed genes from H226 treated with DMSO and H226 with short term GNE-7883 treatment. Hallmark MSigDB pathways are shown with normalized enrichment scores (NES) of indicated pathways on the x-axis and q-values (FDR < 0.05) indicated by color scale. F Representative EdU incorporation assay images of H226 cells treated with DMSO or 1 μM GNE-7883 for 48 h (Scale bar: 20 μm); n = 3 biological replicates. G (Top, center) Density scatter plots of H226 cells treated with DMSO or GNE-7883 for 48 h. EdU-negative cells represent G1 phase, EdU-positive cells indicate S phase (n = 1000 cells per condition); The color scale represents cell density. (Bottom) Quantification of (G). Statistical significance was assessed using one-way ANOVA followed by posthoc Tukey’s test. Data are presented as mean values ± SD; n = 3 biological replicates. H Heatmap representation of downregulated ATAC-seq peaks in H226 cells following 48 h treatment with DMSO, GNE-7883 or GNE-6915. I Venn diagrams showing overlap between differentially downregulated (left) or upregulated (right) ATAC-seq peaks of GNE-7883 and GNE-6915 compared to DMSO control (FDR < 0.05 and fold change > 1.5). J Top known motifs enriched in downregulated peaks after GNE-7883 or GNE-6915 treatment analyzed with HOMER. Shown are HOMER binomial P values. Source data are provided as a Source Data file.

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