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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752
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Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752

机译：MET的扩增可能会鉴定出对选择性酪氨酸激酶抑制剂PHA-665752极为敏感的癌症子集

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The success of molecular targeted therapy in cancer may depend on the selection of appropriate tumor types whose survival depends on the drug target, so-called "oncogene addiction." Preclinical approaches to defining drug-responsive subsets are needed if initial clinical trials are to be directed at the most susceptible patient population. Here, we show that gastric cancer cells with high-level stable chromosomal amplification of the growth factor receptor MET are extraordinarily susceptible to the selective inhibitor PHA-665752. Although MET activation has primarily been linked with tumor cell migration and invasiveness, the amplified wild-type MET in these cells is constitutively activated, and its continued signaling is required for cell survival. Treatment with PHA-665752 triggers massive apoptosis in 5 of 5 gastric cancer cell lines with MET amplification but in 0 of 12 without increased gene copy numbers (P = 0.00016). MET amplification may thus identify a subset of epithelial cancers that are uniquely sensitive to disruption of this pathway and define a patient group that is appropriate for clinical trials of targeted therapy using MET inhibitors.
机译：分子靶向疗法在癌症中的成功可能取决于对适当肿瘤类型的选择，其存活取决于药物靶标，即所谓的“致癌基因成瘾”。如果要针对最易感患者群体进行初始临床试验，则需要临床前方法来定义药物反应性亚组。在这里，我们显示具有高水平稳定的生长因子受体MET染色体扩增的胃癌细胞对选择性抑制剂PHA-665752非常敏感。尽管MET激活主要与肿瘤细胞迁移和侵袭性有关，但这些细胞中扩增的野生型MET被组成性激活，其持续的信号传导是细胞存活所必需的。用PHA-665752进行的治疗在MET扩增的5种胃癌细胞株中有5种触发了大规模凋亡，而在12种中的0种中却没有增加基因拷贝数（P = 0.00016）。因此，MET扩增可鉴定出对该途径的破坏独特敏感的上皮癌的子集，并确定了适合使用MET抑制剂进行靶向治疗的临床试验的患者组。

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