A systems biology approach to define pathways of oxaliplatin and 5-fluorouracil resistance in colorectal cancer

The discovery of underlying mechanisms of drug resistance and the development of novel agents to target these pathways is a priority for patients with advanced colorectal cancer (CRC). The aim of this study was to identify novel targets whose knock-down is important in mediating sensitivity to 5-FU and oxaliplatin in Kras wild type and mutant CRC models. Materials and Methods. Transcriptional profiling (Almac Diagnostics Colorectal Cancer Disease Specific Array'") of pre-treatment metastatic CRC liver biopsies and oxaliplatin/5-FU resistant HCTl16 cell lines followed by Pathway Analysis and Gene Set Enrichment Analysis (GSEA) were used to identify individual genes from novel drug-sensitivity pathways for incorporation into a RNAi screen. Results. We identified panels of genes whose expression is altered (acutely and basally) between sensitive and 5-FU- or oxaliplatin-resistant models. The significant pathways involved in 5-FU/oxaliplatin resistance included Cell Cycle, Focal Adhesion, Insulin and MAPK signalling. In the MAPK pathway, we found that FGFR4 silencing potently increased apoptosis in Kras wild type and mutant CRC cells, and this was further enhanced when FGFR4 siRNA was combined with 5-FU or oxaliplatin. FGFR4 inhibition completely inhibited migration of Kras mutant HCTl16 cells and we found that FGFR4 silencing resulted in strong inhibition of ST A T3 activity in Kras mutant, but not Kras wild type, CRC cells. Conclusions. This study demonstrates the utility of microarray expression data, obtained from pre-clinical and clinical samples, and analyzed by pathway and Gene Set Enrichment Analysis to identify pathways of oxaliplatin/5-FU sensitivity in CRC. In addition FGFR4 inhibition in combination with 5-FU or oxaliplatin could represent a novel treatment strategy for Kras mutant and wild type CRC tumours. We are currently investigating FGFR4 small molecule inhibitors in preclinical in vitro and in vivo models.EThOS - Electronic Theses Online ServiceGBUnited Kingdo