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. 2017 Sep 19;8:607. doi: 10.1038/s41467-017-00452-4

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© The Author(s) 2017

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 7 — Increased expression of IGF-1, FGFR-3, its ligand FGF-2 and CD20 in tumor tissue obtained on treatment with BRAF and MEK inhibitors. a, b Tumor tissue from melanoma patients (n = 20) after kinase inhibitor therapies (red bars) show increased transcript levels of IGF-1, FGFR-3, CD20, and FGF-2 b when compared with same patients’ pre-treatment tumor tissues (black bars). mRNA transcripts were determined by real time qPCR (as described in Fig. 1 legend) with levels indicated as RQ values normalized to an endogenous control (GAPDH) and relative to pre-treatment cDNA samples. c Transcript levels of IGF-1, FGFR-3, and CD20 of melanoma patients’ cDNA samples on treatment showed a correlation with each other (IGF-1 and FGFR-3 (Spearman’s r = 0.6936; p = 0.0376); IGF-1 and CD20 (Spearman’s r = 0.5074; p = 0.0020)). d Increased presence of CD20⁺ B cells co-stained with IGF-1 in tumor sections obtained from patients undergoing treatment with kinase inhibitors. Representative immunostaining of a patient’s tumor section pre- (left top panel) and on-therapy (bottom left panel) with BRAFi/MEKi showing co-staining of IGF-1 (red) and CD20 (dark brown). Magnified view of the co-staining is shown on top right panel and multi-spectral analysis confirming the co-localization of IGF-1 and CD20+ B cells is shown in bottom right panel (yellow). Scale bars: 100 μm. e Increased RNA expression of FGFR-3 in 8/21 progression biopsies (green frame) obtained post BRAF inhibitor (dabrafenib) therapy when compared with pretreatment biopsies. Gene expression analysis was performed using GEO data set (GSE50509). f Gene expression analysis of GEO data set (GSE8401, n = 52 metastatic melanoma samples): scatter plots showing significantly higher CD20 RNA expression (two probes; left two panels; p = 0.0185 and p = 0.0125; t-test) (see also Supplementary Fig. 11) and a trend towards higher IGF-1 expression (two probes; right two panels) in therapy resistant samples. g RNA-seq data were downloaded from EGA under accession number EGAS00001000992 (n = 38 melanoma samples, 27 patients) and the data from multiple probe sets are summarized into scatter plots. Significantly higher CD20 (MS4A1; left panel; p = 0.0206) and IGF-1 RNA expression (right panel; p = 0.0403; t-test) are seen in BRAFi-resistant melanomas