Abstract
Background:
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 fibroblast growth factor receptor 4 (FGFR4) is frequently overexpressed in solid tumours, such as CRC, and has been shown to be an important regulator of cancer cell growth and motility. 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 (WT) and mutant (MT) CRC models.
Methods:
Transcriptional profiling (Almac Diagnostics CRC Disease Specific Array) of pre-treatment metastatic CRC liver biopsies and oxaliplatin/5-FU resistant HCT116 cell lines followed by Metacoreä 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 in vitro and clinical 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 KrasWT and MT CRC cells, and this was further enhanced when FGFR4 siRNA was combined with 5-FU or oxaliplatin. Interestingly, FGFR4 inhibition completely inhibited migration of KrasMT HCT116 cells. Mechanistically, we found that FGFR4, silencing resulted in strong inhibition of STAT3 activity in both KrasWT and MT 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 KrasMT and WT CRC tumours. We are currently investigating FGFR4 small molecule inhibitors in preclinical in vitro and in vivo models.
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 fibroblast growth factor receptor 4 (FGFR4) is frequently overexpressed in solid tumours, such as CRC, and has been shown to be an important regulator of cancer cell growth and motility. 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 (WT) and mutant (MT) CRC models.
Methods:
Transcriptional profiling (Almac Diagnostics CRC Disease Specific Array) of pre-treatment metastatic CRC liver biopsies and oxaliplatin/5-FU resistant HCT116 cell lines followed by Metacoreä 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 in vitro and clinical 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 KrasWT and MT CRC cells, and this was further enhanced when FGFR4 siRNA was combined with 5-FU or oxaliplatin. Interestingly, FGFR4 inhibition completely inhibited migration of KrasMT HCT116 cells. Mechanistically, we found that FGFR4, silencing resulted in strong inhibition of STAT3 activity in both KrasWT and MT 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 KrasMT and WT CRC tumours. We are currently investigating FGFR4 small molecule inhibitors in preclinical in vitro and in vivo models.
| Original language | English |
|---|---|
| Journal | Journal of Clinical Oncology |
| Publication status | Published - 2011 |
| Externally published | Yes |