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Fig. 4 | Journal of Experimental & Clinical Cancer Research

Fig. 4

From: Cancer-related CD15/FUT4 overexpression decreases benefit to agents targeting EGFR or VEGF acting as a novel RAF-MEK-ERK kinase downstream regulator in metastatic colorectal cancer

Fig. 4

CD15/FUT4 transcript is repressed by MEK inhibitors in CRC cell lines with intrinsic resistance to cetuximab or bevacizumab. a Heat map showing groups of differentially expressed genes or “responsive genes” to the MEK inhibitor “AZD6244, Selumetinib” (MEKi) or control, in a metastatic, KRAS mutant and cetuximab-resistant CRC line “SW480”. Down-regulated expression of CD15/FUT4 in “Selumetinib” treated cells, shows a high level of concordance with genes implicated in DNA replication (MCM) and immune-escape mechanisms (CD47, CD73) (gene signature a and b, respectively). The gene signature (b) indicates MEKi upregulated genes mainly involved in cell-cycle arrest (CDKN) or tumor differentiation (CDX2, CDH1, MUC1). b Number and distribution of differentially expressed genes (DEGs) between the MEK inhibitor responsive genes and CD15/FUT4-related genes derived from (TCGA data set). c Six CRC cell lines, HT29, LoVo, SW480, SW620, HCT116, SW48 and GEO treated for 96 h with indicated MEKi are subdivided taking into account CD15/FUT4 expression levels. Results represent the mean of the IC50 ± SD determined by interpolation from the dose response curves in CD15/FUT4-high (HT29, LoVo, SW480 and SW620) and CD15/FUT4-low (HCT116, SW48 and GEO) expressing CRC cells. HT29, LoVo, SW480 and SW620 cells are known for intrinsic resistance (R) to cetuximab or bevacizumab. d Simplified model showing CD15/FUT4 activation as a novel RAF-MEK-ERK signaling cascade downstream regulator. CD15/FUT4 could promote two mechanisms of primary resistance to agents targeting EGFR and VEGF cell proliferation (prosurvival) and evasion of immune surveillance likely through several pathways consisting of ERBB3, FGFR and IL1b cascade. The combined blockade of EGFR or VEGF with MEKi could represent a therapeutic strategy for preventing and/or overcoming resistance of CD15/FUT4-overxpressing tumors

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