Fig. 5: Increased AR expression perturbs the transcriptional response of melanoma cells to BRAFi.

a Transcriptional response of melanoma cells plus/minus AR overexpression to acute BRAFi treatment. Volcano plot of transcriptional changes consistently elicited in A375, M14, and WM9 melanoma cells infected with control (LacZ expressing) (left) or AR overexpressing (right) lentiviruses by 48 h of treatment with Dabrafenib (0.5 μM) versus DMSO. The x-axis shows the fold change (log₂), and the y-axis shows the p-value (−log₁₀). Colored dots correspond to genes with a p-value < 0.05, two-tailed t-test, and log₂fold-change threshold of −1 and 1. Magenta and cyan dots correspond to genes similarly and specifically modulated by DAB treatment in control versus AR overexpressing melanoma cells, respectively. Indicated are TGF-ß and EGFR families. The list of modulated genes in the three melanoma cell lines is provided in Supplementary Data 2. b Functionally relevant GO families significantly downmodulated by BRAFi treatment in both control and AR overexpressing cells (upper), and GO families upmodulated only in AR overexpressing cells (middle) or in control cells (bottom). The -log ₁₀(p-value) is indicated by the heatmap color scale, two-tailed t-test. The list of modulated gene families is in Supplementary Data 2. c–f GSEA of transcriptional profiles of control melanoma cells (A375, M14, and WM9) plus/minus DAB treatment and of DAB-treated control versus AR overexpressing cells using predefined gene signatures of interferon alpha and gamma response c, d and antigen processing and presentation e, f derived from the hallmark gene set (HM)²² and KEGG⁵⁵ collections. Genes are ranked by signal-to-noise ratio in DAB versus DMSO-treated melanoma cells; the position of individual genes is indicated by black vertical bars; the enrichment pattern is in green. In e, f, GSEA and the leading-edge analysis of the antigen processing and presentation signature are shown in each of the three melanoma lines plus/minus DAB treatment e and of DAB-treated control versus AR overexpressing cells f.