Extended Data Fig. 9: The reactivated MAPK pathway in RTT tumours has a qualitatively and quantitatively different output. | Nature Cancer

Extended Data Fig. 9: The reactivated MAPK pathway in RTT tumours has a qualitatively and quantitatively different output.

From: Acquired resistance to anti-MAPK targeted therapy confers an immune-evasive tumor microenvironment and cross-resistance to immunotherapy in melanoma

Extended Data Fig. 9

a, HOMER motif enrichment analysis of upregulated genes comparing RTT vs. NTT tumours of indicated models. b, Heatmap of normalized (RPGC) gene accessibility tracks. Depicted are accessibility profiles for peaks containing motifs of MAPK effectors (left, containing any of the following motifs: AP-1, Fosl2, Fra1, Fra2, Jun-AP-1, c-Jun-CRE, JunB, JunD, ATF2, ATF3) or peaks without MAPK motifs (right). c, Scheme illustrating workflow of SLAM-seq experiment in NTT and RTT (RAFi resistant) Braf/PtenOVA melanoma. d, pERK status in NTT and RTT Braf/PtenOVA melanoma, 1-hour post exposure to MEKi. Experiment performed twice; representative example shown. e, PCA Plot highlighting the Top 500 most variable genes (based on reads containing TC conversions) in SLAM-seq dataset. f, Changes in abundance of newly synthesized mRNA (detected in SLAM-seq based on T > C conversions) in NTT (left) or RTT (right) Braf/PtenOVA melanoma treated with MEKi for 2 hours. Significant targets genes identified in SLAM-seq in NTT cells (black), RTT cells (red) or both (blue) are labelled. Only genes with >2RPMu in CTRL or MEKi conditions displayed. g, Expression of newly synthesized mRNA (RPMu) of 488 target genes identified with SLAM-seq (log2FC < −1, >1, padj<0.1, >2 RPMu) in NTT and RTT Braf/PtenOVA melanoma ± MEKi. Target genes are grouped according to their expression change upon MEKi in both cell lines. (NTT: genes that change expression upon MEKi only in NTT cell line (RTT FC < 1.5), RTT: genes that change expression upon MEKi only in RTT cell line (RTT FC < 1.5), Common: gene expression FC upon MEKi exceeds ±1.5 in both cell lines). h, Expression of selected immune-related genes in NTT, RTT and RTT + MEKi (72 h) sorted Braf/PtenOVA melanoma cells from Rag2-/- mice (NTT, n = 3 RTT, n = 8; RTT + MEKi n = 6 tumours). i, PCA plot displaying top 500 most variable genes for Braf/PtenOVA melanoma cells sorted from NTT and RTT tumours after 72 h of MEKi or CTRL treatment.

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