title: Fibroblast growth factor receptor 4 (FGFR4): a targetable regulator of drug resistance in colorectal cancer.
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.
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: R C
authors: RC
authors: Turkington
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: D B
authors: DB
authors: Longley
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: W L
authors: WL
authors: Allen
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: L
authors: L
authors: Stevenson
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: K
authors: K
authors: McLaughlin
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: P D
authors: PD
authors: Dunne
authors: Department of Bioinformatics, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: J K
authors: JK
authors: Blayney
authors: Department of Molecular Pathology, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: M
authors: M
authors: Salto-Tellez
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: S
authors: S
authors: Van Schaeybroeck
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: P G
authors: PG
authors: Johnston
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D010671:Phenylurea Compounds / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C568950:infigratinib; D051499:Receptor, Fibroblast Growth Factor, Type 4; D020169:Caspases; D005472:Fluorouracil