Abstract
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). We previously undertook a systems biology approach to design a functional genomic screen and identified fibroblast growth factor receptor 4 (FGFR4) as a potential mediator of drug resistance. The aim of this study was to examine the role of FGFR4 in drug resistance using RNAi and the small-molecule inhibitor BGJ398 (Novartis). We found that FGFR4 is highly expressed at the RNA and protein levels in colon cancer tumour tissue compared with normal colonic mucosa and other tumours. Silencing of FGFR4 reduced cell viability in a panel of colon cancer cell lines and increased caspase-dependent apoptosis. A synergistic interaction was also observed between FGFR4 silencing and 5-fluorouracil (5-FU) and oxaliplatin chemotherapy in colon cancer cell lines. Mechanistically, FGFR4 silencing decreased activity of the pro-survival STAT3 transcription factor and expression of the anti-apoptotic protein c-FLIP. Furthermore, silencing of STAT3 resulted in downregulation of c-FLIP protein expression, suggesting that FGFR4 may regulate c-FLIP expression via STAT3. A similar phenotype and downstream pathway changes were observed following FGFR4 silencing in cell lines resistant to 5-FU, oxaliplatin and SN38 and upon exposure of parental cells to the FGFR small-molecule inhibitor BGJ398. Our results indicate that FGFR4 is a targetable regulator of chemo-resistance in CRC, and hence inhibiting FGFR4 in combination with 5-FU and oxaliplatin is a potential therapeutic strategy for this disease.
Highlights
fibroblast growth factor receptor 4 (FGFR4) is one of a family of highly conserved tyrosine kinase receptors that regulate cellular pathways involved in proliferation, differentiation and survival.[3]
Given the role of caspase 8 in siRNA targeting FGFR4 (siFGFR4)-induced apoptosis and the downregulation of the endogenous inhibitor of caspase 8, cellular FLICE-inhibitory protein (c-FLIP), we examined the effect of FGFR4 silencing in the c-FLIPL overexpressing cell line FL17.30 Flow cytometric analysis demonstrated that the FL17 cell line was significantly more resistant to siFGFR4-induced apoptosis compared with the parental HCT116 cell line (Po0.001, Figure 5c)
A role for FGFR4 has been described in the resistance of breast cancer cells to the DNA-damaging agents doxorubicin and cyclophosphamide.[27]
Summary
FGFR4 is one of a family of highly conserved tyrosine kinase receptors that regulate cellular pathways involved in proliferation, differentiation and survival.[3]. Received 07.10.13; revised 21.12.13; accepted 23.12.13; Edited by H-U Simon as an oncogene in breast cancer cell lines and activating mutations occur in up to 7% of rhabdomyosarcoma (RMS) tumours during tumourigenesis.[19,20] In other tumour types, FGFR4 mutations are infrequent, but the single-nucleotide polymorphism FGFR4 G388R increases stability, prolongs activation of the receptor, and is associated with a poor prognosis in melanoma, breast, prostate and head and neck cancers.[21,22,23,24] In colon cancer, FGFR4 has an important role in tumour–stroma interaction and the presence of the FGFR4 G388R substitution correlates significantly with advanced tumour stage and lymph node metastases.[21,25] Inhibition of FGF19-FGFR4 signalling in colon cancer using an FGF19 blocking antibody (IA6) has been shown to disrupt FGF19 binding to FGFR4, inhibiting the growth of HCT116 and Colo[201] xenograft tumours.[26] In relation to chemo-resistance, a role for FGFR4 has recently been described, with upregulation of FGFR4 in response to the DNA-damaging agent Doxorubicin.[27]. Our results indicate the influential role played by FGFR4 in CRC and the potential importance of targeting this receptor as a strategy to overcome drug resistance
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