Abstract 1916: Blockade of the fibroblast growth factor receptor (FGFR) system by the novel FGFR inhibitor BGJ398 modulates oncogenic signaling in human gastric cancer cells, endothelial cells and pericytes

Abstract

Abstract Expression of the FGFR system has been associated with poor prognosis in patients suffering from gastric cancer. Moreover, activation of FGFRs has been demonstrated to mediate tumor angiogenesis through regulation of endothelial cell (EC) and pericyte motility and survival. Therefore, in this study we sought to investigate the effects of targeting FGFR on gastric cancer cells as well as on important components of the tumor microenvironment by the novel FGFR inhibitor BGJ398. For the experiments, human gastric cancer cell lines (TMK-1 and KKLS) as well as ECs and pericytes (vascular smooth muscle cells, VSMCs) were used. The FGFR inhibitor BGJ398 was provided by Novartis Oncology (Basel, Switzerland). Effects of BGJ398 on tumor cell growth and chemoresistance were determined by MTT assays. Impact of BGJ398 on motility of cancer cells was evaluated by modified Boyden chambers. Signaling pathways affected by BGJ398 treatment were assessed by Western blot analyses. To determine effects of FGFR blockade on ECs and pericytes conditioned media from gastric cancer cells was used. Results show that targeting FGFR by BGJ398 impaired growth of gastric cancer cells in a dose-dependent manner in vitro. Furthermore, activation of Akt and Erk in cancer cells was effectively inhibited while expression of c-Myc and HIF-1α was substantially reduced. Additionally, therapy with BGJ398 led to significant inhibition of constitutive migratory and invasive properties of gastric cancer cells (P<0.05). Interestingly, interference with FGFR by BGJ398 increased sensitivity for chemotherapy with oxaliplatin and 5-FU in tumor cells. In ECs as well as pericytes blockade of FGFR by BGJ398 significantly inhibited cell growth and motility even upon stimulation with conditioned media (P<0.05). In conclusion, inhibition of the FGFR system by BGJ398 disrupts oncogenic signaling, impairs tumor cell motility and improves chemosensitivity in gastric cancer. Furthermore, antiangiogenic effects might be mediated via direct effects on ECs and pericytes. Hence, targeting the FGFR system may represent a promising approach to improve current therapy strategies for gastric cancer and warrants further preclinical evaluation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1916. doi:1538-7445.AM2012-1916