Presentation Authors: Takafumi Narisawa*, Sei Naito, Hiromi Ito, Toshihiko Sakurai, Osamu Ichiyanagi, Tomoyuki Kato, Yamagata, Japan, Peter Makhov, Vladimir Kolenco, Philadelphia, PA, Norihiko Tsuchiya, Yamagata, Japan
Introduction: Whole genome analyses have showed that fibroblast growth factor type 4 (FGFR4) gene amplification is widespread (around 60%) in clear cell renal cell carcinoma (ccRCC). Our objectives are to investigate the effects of FGFR4 and the potential for therapeutic target in ccRCC.
Methods: The correlation between FGFR4 copy number (CN) and protein expression in ccRCC cell lines (A498, A704, and 769P) and clinical ccRCC specimens were estimated. CN was estimated using quantative real time polymerase chain reaction (qRT-PCR). Protein expressions in cell lines are evaluated using western blotting (WB) and ones in surgical specimens were done using immunohistochemistry (IHC). To investigate the roll of FGFR4 in ccRCC cells, WB, MTS assay and apoptotic assay were performed with or without FGFR4 inhibition by siRNA and pharmacological inhibitor BLU9931 treatment. To evaluate the potential for therapeutic target, BLU9931 administration for xenograft mouse model was performed.
Results: IHCs showed FGFR4 expression in the cancer area was stronger than in the normal area (Fig 1.). FGFR4 protein expression was positively correlated with genetic amplification in cell lines and surgical specimens (Fig 2.). FGFR4 inhibition using siRNA or BLU9931 (1) suppressed phosphorylation of Akt and ERK1/2, (2) suppressed cell proliferation (Fig 4.), and (3) induced apoptosis in vitro. BLU9931 administration for xenograft mouse model suppressed tumor growth and caused apoptosis under the tolerable dose (Fig 5.).
Conclusions: FGFR4 is strongly expressed in ccRCC with FGFR4 genetic amplification. FGFR4 is a proliferative driver in ccRCC and the potential as a new therapeutic target.
Source of Funding: JSPS KAKENHI Grant Number 16K18448