FGFR4 increases EGFR signaling by inducing AREG expression and attenuates response to EGFR inhibitors in colon cancer

Fibroblast growth factor receptor 4 (FGFR4) is known to induce cancer cell proliferation, invasion, and anti-apoptosis via activation of RAS/RAF/ERK and PI3K/AKT pathways, which are also known as major molecular bases of colon cancer carcinogenesis related with EGFR signaling. However, the interaction of FGFR4 and EGFR signaling in regard to colon cancer progression is unclear. Here, we investigated a potential crosstalk between FGFR4 and EGFR, and the effect of anti-EGFR therapy in colon cancer treatment. To explore the biological roles of FGFR4 in cancer progression, RNA-seq was performed using the FGFR4 transfected colon cell lines. Gene ontology data showed the upregulation of genes related to EGFR signaling and we identified that FGFR4 overexpression secrets EGFR ligands such as AREG with consequent activation of EGFR and ErbB3. This result was also shown in in vivo study and the cooperative interaction of EGFR and FGFR4 promoted tumor growth. In addition, FGFR4 overexpression reduced cetuximab induced cytotoxicity and the combination of FGFR4 inhibitor (BLU9931) and cetuximab showed profound antitumor effect than cetuximab alone. Clinically, we found the positive correlation between FGFR4 and AREG expression in tumor tissue, but not in normal tissue from colon cancer patients and these expressions were significantly correlated with poor overall survival in patients treated with cetuximab. Therefore, our results provide the novel mechanism of FGFR4 in connection with EGFR activation and the combination of FGFR4 inhibitor and cetuximab may be a promising therapeutic option to achieve the optimal response to anti-EGFR therapy in colon cancer.