Gene expression analysis of TPC1 cells treated with a RET inhibitor identifies adaptive resistance signature. (A) Venn overlap of differential gene expression in TPC1 cells treated with the indicated drug combinations. (A) Set of 63 genes identified as correlated with adaptive resistance to BLU6864 and sensitivity to the combination of BLU6864 and BGJ398. (B) Heatmap of 63 gene resistance signature across treatment conditions. (C) Top differentially regulated pathways from 63 gene resistance signatures identified using gProfiler. (D) GSEA using response to FGF as a signature in BLU6864 (24 h) vs. BLU6864 (6 h; top), compared with BGJ398 + BLU6864 (24 h) vs. BLU6864 (24 h; bottom). NES, normalized enrichment score. (E) NESs from GSEA plotted for selected GO signatures. Differential gene expression from BLU6864 (24 h) vs. BLU6864 (6 h) is plotted in blue and compared with BGJ398 + BLU6864 (24 h) vs. BLU6864 (24 h), plotted in green. Light blue shading indicates a nonsignificant result (P > 0.05, FDR > 0.2), and dark blue shading indicates a significant result (P < 0.05, FDR < 0.2). Statistical tests were performed using the GSEA software.