Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma - PubMed (original) (raw)

AhR signature correlates with dedifferentiation states of melanoma cell lines and resistance to BRAFi. a Expression heatmap for β- and α-signature genes in different Vem-sensitive or -resistant melanoma cell lines from the Cancer Cell Line Encyclopedia RNAseq dataset (GEO, GSE36134). IC50 values for PLX4720 were obtained from Supplementary Table 7 of ref. . Genes and clusters with similar expression profiles across the cohort are placed close to each other in the grid. b Expression heatmap for BRAFi resistance genes in different Vem-sensitive or -resistant melanoma cell lines from Cancer Cell Line Encyclopedia RNAseq dataset (GEO, GSE36134) (top) and average signatures for the α- (established by the median of expression of AhR target genes: INHBA, THBS1, RUNX2, REEP2, PMAIP1, OSMR, LRRC49, and CYP1B1), for the β- (established by the median of expression of pigmentation genes: GPR143, TYR, SLC45A2, RAB38, SNCA, MLPH, MLANA, and MITF), and for the resistance genes (AXL, GCNT1, NRP1, ZEB1, ITGA1, and LPAR1) (mid). Differentiation status for melanoma cell lines consistent with the four-stage differentiation model (melanocytic: M, transitory: T, neural crest-like: N, and undifferentiated: U) has been established for the different melanoma cell lines considering average signature from subtype genes described in supplemented files from Tsoi et al. (bottom). c Expression heatmap for β-, α-, and resistance genes signatures in the melanoma cultures dataset from the GEO dataset (GSE60664) depending on their proliferative or invasive states. Average signatures and differentiation status for melanoma cell lines have been indicated at the bottom. d PCA of melanoma cell line datasets obtained by the cluster prediction assignment (from melanoma dedifferentiation signature resource from Graeber’s lab:

http://systems.crump.ucla.edu/dediff/

). e–g MLANA, PMAIP1, and AXL expression PCA color maps illustrating, respectively, β- (e), α- (f), and resistance signatures (g) from different subtypes of melanoma cell lines dataset from Graeber’s lab (top). Boxplots of selected β-genes (as described above) in different subtypes of melanoma cell lines (U, undifferentiated; N, neural crest-like; T, transitory; M, melanocytic) (bottom). Number in each group: U = 10, N = 14, T = 12, M = 17. Whiskers reflect median of expression with range. One-way ANOVA and Tukey’s test: ***p < 0.001, ****p < 0.0001. h Fold expression level (log2) for average β-, α-, and resistance genes signatures in different melanoma cell lines from the lab compared to the 501Mel cell line (top). Vem sensitivity has been established by cell density measurement and calculation of the IC50 (bottom) using GraphPad (PRISM6.0®) 4 days after every 2 days of treatment with an increasing concentration of Vem. Asterisk: NRAS mutant