Identification of a novel oncogenic mutation of FGFR4 in gastric cancer

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.

Identification of a novel FGFR2-KIAA1217 fusion in esophageal gastrointestinal stromal tumours: A case report

“…Also, FGFR4, another member of FGFR family, has gradually been noticed. Indeed, while it is well known that its mutations are recurrent in several pediatric and adult rhabdomyosarcoma cases ( 24 ), recently its role has been proved also in gastric cancers, showing that mutationally activated FGFR4 may act as an oncoprotein, therefore supporting its therapeutic targeting ( 25 ). Therefore, FGFR-specific tyrosine kinase inhibitors may also provide a new approach to treating GISTs with FGF/FGFR pathway mutations.…”

Biological Significance and Targeting of the FGFR Axis in Cancer

“…These mutations can alter the ligand binding, juxtamembrane and kinase domains and constitutively activate FGFR or impair FGFR degradation, leading to increased FGFR signalling (as reviewed by [111,[145][146][147]. FGFR4 activating mutations are not detected very often, apart from in rhabdomyosarcoma [148] and gastric cancer [149]. Interestingly, some of the activating mutations can result in changes in the efficacy of several inhibitors that can target FGFR, such as AZD4547, BGJ-398, KTI258, AP24534 and JNJ42756493 [150].…”

FGFR Fusions in Cancer: From Diagnostic Approaches to Therapeutic Intervention

“…FGFR4-activating mutations are rare and are detected in some pediatric tumors, such as rhabdomyosarcoma [22]. A novel oncogenic mutation of FGFR4 (G636C) has been recently discovered in gastric cancer [23].…”