Abstract 1643: AZD4547, a potent and selective inhibitor of FGF-receptor tyrosine kinases 1, 2 and 3, inhibits the growth of FGF-receptor 2 driven gastric cancer models in vitro and in vivo
| Autor: | Maggie Wang, Liang Xie, Jessie Xu, Xinying Su, David Zhang, Lily Tang, Zengquan Wang, Jingchuan Zhang, Qunsheng Ji, Lucy Yin, Katherine Ye, Elaine Kilgour |
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| Rok vydání: | 2011 |
| Předmět: | |
| Zdroj: | Cancer Research. 71:1643-1643 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2011-1643 |
| Popis: | Gastric cancer is the second most lethal cancer worldwide. We and others have shown that the FGFR2 gene is amplified in a subset of gastric cancers. To validate FGFR2 as a potential therapeutic target for gastric cancer, we employed an inducible shRNA system to specifically block expression of individual FGFRs, both in vitro and in vivo. When FGFR2 was specifically down regulated in an FGFR2-amplified gastric cancer cell line Snu-16, the activation of pFGFR2 and its downstream signaling effectors were blocked and there was significant inhibition of the cell growth and survival that further translated into tumor growth regression in vivo, demonstrating that in this model tumor growth/survival is dependent on the FGFR2 pathway. To further confirm this, AZD4547, a selective inhibitor of FGFR 1, 2 and 3 receptor tyrosine kinases was tested in a panel of gastric cancer cell lines for its anti-proliferative effect. In this panel the cell-lines that were most sensitive to AZD4547 were the Snu-16 and KATOIII, both of which are gene amplified for FGFR2. Exposure of the Snu-16 cells to AZD4547 resulted in cell-death and once daily oral dosing of AZD4547 resulted in tumor growth inhibition of the Snu-16 xenografts in a dose-dependent fashion, with significant tumor regression observed when AZD4547 was dosed once daily at 12.5 mg/kg. The anti-tumor efficacy of AZD4547 correlated with inhibition of pFGFR2 and modulation of other downstream markers of FGFR pathway activation, including pErk, pS6 protein and pPLCγ and efficacious doses of AZD4547 induced elevations of levels of plasma FGF23, a known marker of FGFR inhibition. In addition to the single-agent efficacy, combining of AZD4547 with cytotoxic agents, currently used for the treatment of gastric cancer patients, revealed enhanced growth inhibition of Snu-16 xenografts. Taken together, these data support clinical testing of AZD4547 in gastric cancer patients harboring FGFR2 gene amplification. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1643. doi:10.1158/1538-7445.AM2011-1643 |
| Databáze: | OpenAIRE |
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