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Identification of a novel oncogenic mutation of FGFR4 in gastric cancer
Takashi Futami1, Tatsuya Kawase2, Kenichi Mori2
1Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan. takashi.futami@astellas.com.
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.
Insights
A novel oncogenic mutation in FGFR4 (G636C) was identified in gastric cancer, leading to its constitutive activation. This mutation represents a potential therapeutic target for advanced gastric cancer, showing promise with FGFR inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Gastric cancer is a leading cause of cancer mortality globally.
- Current treatments for advanced or recurrent gastric cancer offer limited improvement in patient prognosis.
- There is a critical need for novel therapeutic strategies.
Purpose of the Study:
- To identify and characterize oncogenic mutations in gastric tumours.
- To investigate the functional consequences of identified mutations in FGFR4.
- To evaluate the therapeutic potential of targeting activated FGFR4 in gastric cancer.
Main Methods:
- Screening of human gastric tumours for mutations in FGFR4.
- Expression of wild-type and mutant FGFR4 in NIH/3T3 cells to assess functional effects.
- 3D-structural analysis and molecular modeling of FGFR4.
- Assessing sensitivity to the FGFR inhibitor ASP5878 in Ba/F3 cell lines and in vivo mouse models.
Main Results:
- A G636C mutation in the FGFR4 tyrosine kinase domain was identified in 1 out of 83 gastric tumours.
- The G636C mutation resulted in constitutive FGFR4 activation, enhanced downstream signaling, and increased anchorage-independent cell growth.
- Structural analysis indicated the mutation destabilizes an auto-inhibitory conformation, promoting kinase activation.
- Tumours with the G636C-FGFR4 mutation showed increased sensitivity to the FGFR inhibitor ASP5878 in vitro and in vivo.
Conclusions:
- Mutationally activated FGFR4 functions as an oncoprotein in gastric cancer.
- The G636C-FGFR4 mutation is a driver of gastric tumour growth.
- Targeting FGFR4 with inhibitors like ASP5878 represents a promising therapeutic strategy for patients with FGFR4-mutated gastric cancer.
