Abstract
Abstract While trastuzumab against HER-2 over-expression is the only approved targeted therapy against gastric cancer, it is important to find the biologically significant genetic aberrations in most of gastric cancer without HER-2 overexpression. We performed phospho-RTK (receptor tyrosine kinase) array in 25 gastric cancer cell lines, and confirmed fibroblast growth factor receptor 2 and 3 (FGFR2, 3) as one of the highly phosphorylated RTKs. Knockdown of FGFR3 with transfecting small interfering RNA (siRNA) induced the decrement of phospho-FGFR (653/654) in a time-dependent manner in cell lines with highly activated FGFR3, Hs746T and SNU-5. While cell cycle analysis and apoptosis assay showed no significant changes, invasiveness and anchorage-independent growth was inhibited after FGFR3 siRNA transfection. Modulation of downstream signaling molecules was observed by western blot after transfecting FGFR3 siRNA in Hs746T and SNU-5 cell lines in comparing with FGFR2 activated cell lines (KATO III, SNU-16) transfected with FGFR2 siRNA, since previous reports showed that FGFR2 amplification is important in gastric cancer in influencing cell proliferation and survival. Phospho-AKT was down-regulated in both FGFR2 and FGFR3 activated cell lines after specific siRNA transfection, implying that gastric cancer cells with FGFR2 or FGFR3 activation might be both dependent on PI3K-AKT-mTOR pathway. When we treated mice bearing subcutaneous SNU-5 tumor xenografts with oral FGFR inhibitor TKI-258 (70mg/kg daily), TKI-258 treated group showed anti-tumor growth and anti-angiogenic effect compared with control group. Immunohistochemistry (IHC) against FGFR3 among 116 N3 gastric cancer patient tissues showed 3+ in 62.9%, while FGFR2 positivity was only 11.2%. In summary, we identified FGFR3 harbors significant biological role in subset of gastric cancer patients as FGFR2. Further studies for validating the efficacy of FGFR inhibition in preselected subset of patients would support the proper development of FGFR inhibitor in gastric cancer. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B196. Citation Format: Choong-kun Lee, Won Suk Lee, Jeong Min Kim, Myung Eun Lee, Kyu Hyun Park, Tae Soo Kim, Hyo Song Kim, Hei-Cheul Jeung, Hyun Cheol Chung, Sun Young Rha. FGFR3 as a potential target for gastric cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B196.
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