FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival
FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival
复制标题
DOI：
10.1158/0008-5472.can-07-5229
复制
发表时间：
2008-04-01
期刊：
影响因子：
11.2
通讯作者：
Lutterbach, Bart
中科院分区：
文献类型：
--
作者：
Kunii, Kaiko;Davis, Lenora;Lutterbach, Bart
已经确定了扩增的FGFR2在胃癌细胞增殖和生存中的关键作用。在一组胃癌细胞系中，成纤维细胞生长因子受体2(FGFR2)在FGFR2扩增的细胞系KatoIII、Snu16和OCUM-2m中高表达并选择性地酪氨酸磷酸化。一种特异性的小分子抑制剂抑制FGFR2蛋白激酶，可选择性地抑制FGFR2扩增的细胞系的生长，导致KatoIII细胞的生长停滞，并显著诱导Snu16和OCUM-2M细胞的凋亡。FGFR2扩增的细胞系中EGFR、Her2和erbB3的磷酸化酪氨酸水平也升高，但Gefitinib或erlotinib不能抑制EGFR磷酸化水平的升高。我们发现，升高的EGFR、Her2和erbB3磷酸化酪氨酸依赖于FGFR2，揭示了EGFR家族激酶是扩增的FGFR2的下游靶点。此外，shRNA到erbB3导致了增殖的丧失，证实了激活的EGFR信号通路的功能作用。这些结果表明，在FGFR2扩增的胃癌细胞系中，FGFR2和EGFR家族信号通路都被激活，以推动细胞的增殖和存活。FGFR2或erbB3信号的抑制剂可能对含有FGFR2扩增的胃癌有治疗作用。
have identified a critical role for amplified FGFR2 in gastric cancer cell proliferation and survival. In a panel of gastric cancer cell lines, fibroblast growth factor receptor 2 (FGFR2) was overexpressed and tyrosine phosphorylated selectively in FGFR2-amplified cell lines KatoIII, Snu16, and OCUM-2M. FGFR2 kinase inhibition by a specific small-molecule inhibitor resulted in selective and potent growth inhibition in FGFR2-amplified cell lines, resulting in growth arrest in KatoIII cells and prominent induction of apoptosis in both Snu16 and OCUM-2M cells. FGFR2-amplified cell lines also contained elevated phosphotyrosine in EGFR, Her2, and Erbb3, but the elevated phosphorylation in EGFR could not be inhibited by gefitinib or erlotinib. We show that the elevated EGFR, Her2, and Erbb3 phosphotyrosine is dependent on FGFR2, revealing EGFR family kinases to be downstream targets of amplified FGFR2. Moreover, shRNA to Erbb3 resulted in a loss of proliferation, confirming a functional role for the activated EGFR signaling pathway. These results reveal that both the FGFR2 and EGFR family signaling pathways are activated in FGFR2-amplified gastric cancer cell lines to drive cell proliferation and survival. Inhibitors of FGFR2 or Erbb3 signaling may have therapeutic efficacy in the subset of gastric cancers containing FGFR2 amplification.