Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state Immunohistochemical analysis.

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Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state Immunohistochemical analysis of vemurafenib‐naïve tumors from three melanoma patients stained for NGFR, MITF, and Ki‐67 (see for patient clinical information). Covariate single‐cell analysis of Ki‐67 versus NGFR measured by immunofluorescence in pre‐treatment, on‐treatment (with dabrafenib and trametinib combination for 2 weeks), and post‐relapse tumor biopsies of a BRAF‐mutant melanoma patient (see for patient clinical information). Cell population histograms representing c‐Jun variations measured by immunofluorescence in the same patient‐matched biopsies as shown in (B). NGFR gene expression changes in 21 matched pairs of pre‐treatment and post‐resistance tumor biopsies analyzed by RNA sequencing. MITF changes are shown for tumors with a post‐resistance NGFR increase (increase = log2 (fold‐change) > 0.5, decrease = log2 (fold‐change) < −0.5, no change = |log2 (fold‐change)| ≤ 0.5). Gene expression data from patients treated with RAF inhibitor, MEK inhibitor, or their combination were analyzed by combining two published datasets (Sun et al, ; Hugo et al, ). Ranked GSEA plots of top KEGG pathways significantly correlated with NGFR expression in 18 matched pairs of pre‐treatment and post‐resistance tumor biopsies (Hugo et al, ). IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY'S PERMISSIONS DEPARTMENT ON PERMISSIONS@WILEY.COM OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE 'REQUEST PERMISSIONS' LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER. Mol Syst Biol, Volume: 13, Issue: 1, First published: 09 January 2017, DOI: (10.15252/msb.20166796)