Fig. 6: High MYC expression is associated with a dampened AR transcriptional program and resistance to AR signaling inhibitors in castration-resistant tumors.

a, b AR activity is inversely correlated with MYC expression in CRPC clinical samples (a Pearson correlation coefficient (ρ) and P value; linear regression ± 95% CI; Source data are provided as a Source Data file) and significantly lower in MYC-high tumors (b Two-way ANNOVA followed by a Tukey–Kramer test; median; box boundaries: 25th and 75th percentiles; whiskers: ± lowest/smallest value no further than 1.5 interquartile range; n = 59; Source data are provided as a Source Data file). c Gene Set Enrichment Analysis (GSEA, Hallmark, P < 0.05 and FDR < 0.1) revealed an enriched MYC transcriptional program (P < 0.001 and FDR < 0.001) and a depleted AR response (P < 0.001 and FDR < 0.001) in MYC-high CRPC (Source data are provided as a Source Data file). d, e MYC-high mCRPC LuCaP patient-derived xenografts (PDXs) have similar levels of AR (d Wilcoxon rank-sum test; n = 8 biologically independent animals; median, whiskers ± min to max; Source data are provided as a Source Data file) but are associated with an expanded AR cistrome as demonstrated by the increased binding intensity across 4 kb intervals at AR gained sites (e). f Motif analysis of MYC-associated AR gained sites reveal ARE and FHRE. g, h AR gained sites are characterized by increased FOXA1 binding (g) and H3K27ac mark (h) in MYC-high mCRPC LuCaP. i AR cistrome in MYC-high mCRPC LuCaP PDXs is associated with a diminished androgen response (GSEA; P < 0.001 and FDR < 0.001). j, k Kaplan-Meier curves (j) and univariable analysis (k Cox proportional hazards model) revealed that patients with mCRPC tumors harboring an AR_low/MYC_high signature are more likely to resist ARSI treatment and die of their disease (n = 75; HR ± 95% CI). HR: hazard ratio; CI: confidence interval; NES: normalized enrichment score; ES: enrichment score.