Foretinib (GSK1363089) induces p53-dependent apoptosis in endometrial cancer.
Foretinib (GSK1363089) induces p53-dependent apoptosis in endometrial cancer.
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DOI：
10.18632/oncotarget.25232
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发表时间：
2018-04-27
期刊：
影响因子：
--
通讯作者：
Ohmichi M
中科院分区：
文献类型：
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作者：
Kogata Y;Tanaka T;Ono YJ;Hayashi M;Terai Y;Ohmichi M
Foretinib（GSK1363089或XL880）是一种口服多激酶抑制剂，主要针对肝细胞生长因子（HGF）/Met信号通路而开发，在临床前和临床研究中已显示出对某些癌症的抗肿瘤作用。子宫内膜癌细胞系中的 HGF/Met 信号以自分泌方式受到刺激，对于细胞存活至关重要。用 Foretinib 抑制 HGF/Met 信号传导可在体外诱导子宫内膜癌细胞系中 p53 依赖性细胞凋亡。在使用细胞肿瘤异种移植物的实验中，Foretinib 还显示出显着的体内抗癌作用。在 344 份子宫内膜癌标本中，有 37 份（10.8%）观察到 p53 突变。子宫内膜癌中的 HGF/Met-MAPK/PI3K 通路由 HGF 以自分泌方式激活。 Foretinib 通过抗 Met 磷酸化来诱导抗癌作用，从而诱导 p53 依赖性细胞凋亡；发现 foretinib 在具有野生型 p53 的子宫内膜癌样本中比在具有 p53 突变的样本中发挥更大的抗癌活性。我们的免疫化学分析表明，foretinib 诱导的 p53 依赖性细胞凋亡预计对大约 90% 的子宫内膜癌患者具有治疗潜力。我们评估了子宫内膜癌细胞系中的 HGF/Met 信号通路，并使用体外和体内实验模型评估了福替尼的抗癌作用。此外，对子宫内膜癌标本进行了免疫组织化学分析。
Foretinib (GSK1363089 or XL880), which is an oral multikinase inhibitor developed to primarily target the hepatocyte growth factor (HGF)/Met signaling pathway, has shown anti-tumor effects against some cancers in preclinical and clinical studies. HGF/Met signaling in endometrial cancer cell lines was stimulated in an autocrine manner, and was essential for cell survival. Inhibiting the HGF/Met signaling with foretinib induced p53-dependent apoptosis in endometrial cancer cell lines in vitro. Foretinib also showed significant anti-cancer effects in vivo in experiments using cell tumor xenografts. p53 mutations were observed in 37 (10.8%) of 344 endometrial cancer specimens. The HGF/Met-MAPK/PI3K pathway in endometrial cancer is activated by HGF in an autocrine manner. Foretinib induces an anti-cancer effect through the anti-phosphorylation of Met, which results in the induction of p53-dependent apoptosis; foretinib was found to exert greater anti-cancer activity in endometrial cancer specimens with wild-type p53 than in specimens with p53 mutations. Our immunochemical analysis revealed that foretinib-induced p53-dependent apoptosis can be expected to have therapeutic potential in approximately 90% of endometrial cancer patients. We evaluated the HGF/Met signaling pathway in endometrial cancer cell lines and assessed the anti-cancer effects of foretinib using in vitro and in vivo experimental models. Furthermore, endometrial cancer specimens were subjected to an immunohistochemical analysis.