Abstract
Gastric cancer remains one of the leading causes of cancer death worldwide. Despite intensive investigations of treatments over the past three decades, the poor prognosis of patients with unresectable advanced or recurrent gastric cancer has not significantly changed, and improved therapies are required. Here, we report the identification of an oncogenic mutation in FGFR4 in a human gastric tumour that leads to constitutive activation of its product, FGFR4. The G636C-FGFR4 tyrosine kinase domain mutation was found in 1 of 83 primary human gastric tumours. The G636C mutation increased FGFR4 autophosphorylation, and activated FGFR4 downstream signalling molecules and enhanced anchorage-independent cell growth when expressed in NIH/3T3 cells. 3D-structural analysis and modelling of FGFR4 suggest that G636C destabilizes an auto-inhibitory conformation and stabilizes an active conformation, leading to increased kinase activation. Ba/F3 cell lines expressing the G636C-FGFR4 mutant were significantly more sensitive to ASP5878, a selective FGFR inhibitor, than the control. Oral administration of ASP5878 significantly inhibited the growth of tumours in mice engrafted with G636C-FGFR4/3T3 cells. Together, our results demonstrate that mutationally activated FGFR4 acts as an oncoprotein. These findings support the therapeutic targeting of FGFR4 in gastric cancer.
Highlights
Gastric cancer is an aggressive cancer with poor prognosis and the fifth-most common cause of cancer-related death worldwide[1]
We hypothesized that FGFR4 plays an important role in gastric cancer and that mutations that activate the protein tyrosine kinase activity of FGFR4 promote an aggressive phenotype
We searched for activating FGFR4 mutations of the tyrosine kinase domain in 83 gastric cancer tissue specimens
Summary
Gastric cancer is an aggressive cancer with poor prognosis and the fifth-most common cause of cancer-related death worldwide[1]. 1.2–9% of patients with gastric cancer harbour FGFR2 amplifications associated with increased tumour cell proliferation[6]. We searched for activating FGFR4 mutations of the tyrosine kinase domain in 83 gastric cancer tissue specimens.
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