PLX046924

GSE74729: A novel RAF kinase inhibitor with DFG-out binding mode: high efficacy in BRAF-mutant tumor xenograft models in the absence of normal tissue hyperproliferation

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Purpose: Seek for differential gene expression in vemurafenib-resistant A375 tumors vs. untreated controls to provide a rationale for resistance mechanism; Methods: mRNA profiles of vemurafenib-resistant A375 tumors and untreated control tumors were generated by transcriptome sequencing of A375 melanoma bearing mice. Since our xenograft samples contain a mixture of human and mouse RNAs we mapped RNASeq reads against a hybrid human/mouse genome. We than removed reads of potential mouse origin by taking only reads that map uniquely to human chromosomes. On average 23% of reads were removed as potential mouse reads. We than took the remaining reads (on average 77% per sample) to determine the gene expression levels for each sample. Normalized expression levels of 5 resistant samples were compared to 4 untreated control samples to detect differnetially regulated genes which may contribute to vemurfenib resistance; Results: Expression levels of several genes were consistently altered in all resistant samples. Expression of e.g. genes encoding SPRY2, SPRY4, DUSP6, CCND1, PIK3R3, FGFR1, EPHA4, MCL1, and IGF1R was down-regulated, whereas expression of PDGFC, VEGFC, ABCB9 and KITLG was increased.; Conclusions: Our study reports several differentially expressed genes which may contribute to vemurafenib resistance in A375 tumor bearing mice SOURCE: Andreas Schlattl (andreas.schlattl@boehringer-ingelheim.com) - Boehringer Ingelheim RCV GmbH & Co KG