Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks
Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks
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DOI：
10.1007/s10637-011-9699-0
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发表时间：
2012-08-01
影响因子：
3.4
通讯作者：
Minami, Hironobu
中科院分区：
文献类型：
--
作者：
Kataoka, Yu;Mukohara, Toru;Minami, Hironobu
为了探索foretinib（GSK 1363089）（一种已知靶向MET、罗恩、AXL和血管内皮生长因子受体（VEGF）的口服多激酶抑制剂）在胃癌中的作用机制，我们评价了该药物对以下胃癌细胞系组中细胞生长和细胞信号传导的影响：KATO-III、MKN-1、MKN-7、MKN-45和MKN-74。其中，仅MKN-45和KATO-III分别具有MET和成纤维细胞生长因子受体2（FGFR 2）扩增，对foretinib高度敏感。在MKN-45中，1 μ M foretinib或PHA 665752（另一种MET激酶抑制剂）抑制MET和下游信号分子的磷酸化，如预期。然而，在KATO-III中，PHA 665752独立于下游分子抑制MET的磷酸化。此外，1 μ M的foretinib或PD 173074（一种选择性FGFR激酶抑制剂）可抑制FGFR 2和下游分子的磷酸化，表明foretinib靶向KATO-III中的FGFR 2。我们在OCUM-2 M（另一种FGFR 2扩增的胃癌细胞系）中证实了foretinib对FGFR 2的这种新活性。使用磷酸化受体酪氨酸激酶阵列，我们发现foretinib在MKN-45中通过MET抑制抑制表皮生长因子受体（EGFR）、HER 3和FGFR 3的磷酸化，在KATO-III中通过FGFR 2抑制EGFR、HER 3和MET的磷酸化。用siRNA敲低MKN-45中的HER 3和FGFR 3导致细胞信号传导和细胞生长的部分抑制。总之，foretinib似乎对不仅携带MET而且携带FGFR 2扩增的胃癌细胞有效，并且通过阻断以MET或FGFR 2为核心的RTK间信号网络发挥其抑制作用。
To explore the mechanism of action of foretinib (GSK1363089), an oral multi-kinase inhibitor known to target MET, RON, AXL, and vascular endothelial growth factor receptors (VEGFRs), in gastric cancer, we evaluated the effects of the agent on cell growth and cell signaling in the following panel of gastric cancer cell lines: KATO-III, MKN-1, MKN-7, MKN-45, and MKN-74. Of these, only MKN-45 and KATO-III, which harbor MET and fibroblast growth factor receptor 2 (FGFR2) amplification, respectively, were highly sensitive to foretinib. In MKN-45, 1 mu M of foretinib or PHA665752, another MET kinase inhibitor, inhibited phosphorylation of MET and downstream signaling molecules as expected. In KATO-III, however, PHA665752 inhibited phosphorylation of MET independently of downstream molecules. Further, 1 mu M of foretinib or PD173074, a selective FGFR kinase inhibitor, inhibited phosphorylation of FGFR2 and downstream molecules, suggesting that foretinib targets FGFR2 in KATO-III. We confirmed this novel activity of foretinib against FGFR2 in OCUM-2M, another FGFR2-amplified gastric cancer cell line. Using a phospho-receptor tyrosine kinase array, we found that foretinib inhibits phosphorylation of epidermal growth factor receptor (EGFR), HER3 and FGFR3 via MET inhibition in MKN-45, and EGFR, HER3 and MET via FGFR2 inhibition in KATO-III. Knockdown of HER3 and FGFR3 in MKN-45 with siRNA resulted in the partial inhibition of cell signaling and cell growth. In conclusion, foretinib appears effective against gastric cancer cells harboring not only MET but also FGFR2 amplification, and exerts its inhibitory effects by blocking inter-RTK signaling networks with MET or FGFR2 at their core.