Extended Data Figure 9: Wnt signatures are generally associated with BET resistance and Wnt activation drives resistance of pancreatic cancer models. | Nature

Extended Data Figure 9: Wnt signatures are generally associated with BET resistance and Wnt activation drives resistance of pancreatic cancer models.

From: Transcriptional plasticity promotes primary and acquired resistance to BET inhibition

Extended Data Figure 9

The BETi_Resistance_Rathert signature was defined by combining the core enriched genes from the two significant Wnt gene sets (KEGG_WNT_SIGNALING and ST_WNT_SIGNALING) in murine resistant AML, filtered for significant upregulation (DESeq padj <0.1). These were combined with the Wnt-associated genes found differentially expressed in resistant human leukaemia cell lines and primary patient samples, resulting in a total of 26 genes. a, Left, microarray expression data of all 26 signature genes was curated from the Cancer Cell Line Encyclopedia (CCLE)28 and normalized to the geometric mean of each individual gene throughout all samples (relative expression). The sum of the relative expression of all genes (resistance index) was plotted for all CCLE cell lines showing a GI50 > 450 nM (resistant, 54 total) or a GI50 < 150 nM (sensitive, 55 total) based on our sensitivity profiling (statistical significance was determined using Student’s t-test). Right, gene set enrichment analysis plot comparing the expression of 26 signature genes associated with JQ1 resistance across 54 resistant (GI50 > 450 nM) and 55 sensitive cell lines (GI50 < 150 nM) available from CCLE. b, Left, as in a the resistance index was calculated as the sum of relative expression values of all 26 signature genes, which were based on RPKM extracted from an independent RNA-seq data set27. Plotted are all 49 resistant (GI50 > 450 nM) and all 50 sensitive (GI50 < 150 nM) cell lines analysed in both sensitivity profiling and RNA-seq27 (statistical significance determined using Student’s t-test). Right, gene set enrichment analysis plot comparing the expression of 26 signature genes associated with JQ1 resistance across 49 resistant (GI50 > 450 nM) and 50 sensitive cell lines (GI50 < 150 nM) available from ref. 27. c, Competitive proliferation assays of murine pancreatic adenocarcinoma (KRPC2) cells transduced with pLEPC constructs expressing potent validated shRNAs targeting Apc, cultured in the presence of JQ1 (800 nM) or DMSO. Shown is the relative number of mCherry+ cells over time, relative to initial. d, Cell viability of murine KRPC2 was determined following 5 days of treatment with pyrvinium and/or JQ1 as indicated (n = 3, mean ± s.e.m., statistical significance determined using Student’s t-test). The combination index (CI) for drug combinations was calculated using the CompuSyn software and percentage inhibition (fraction affected, Fa) resulting from combined action of the two drugs versus effects of either drug alone. CI values <1.0 indicate synergism of the two agents. e, As in d, cell viability was determined for human ASPC-1 pancreatic cancer cells following 5 days of treatment with pyrvinium and/or JQ1 as indicated (n = 3, mean ± s.e.m., statistical significance determined using Student’s t-test). The combination index for drug combinations was obtained using percentage inhibition (fraction affected, Fa) resulting from combined action of the two drugs versus effects of either drug alone.

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