Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752
Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752
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DOI：
10.1073/pnas.0508776103
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发表时间：
2006-02-14
影响因子：
11.1
通讯作者：
Haber, DA
中科院分区：
文献类型：
--
作者：
Smolen, GA;Sordella, R;Haber, DA
分子靶向治疗在癌症中的成功可能取决于选择合适的肿瘤类型，这些肿瘤类型的生存取决于药物靶点，即所谓的“癌基因成瘾”。如果最初的临床试验要针对最敏感的患者群体，则需要临床前方法来确定药物反应亚群。在这里，我们表明，具有高水平稳定的染色体扩增的生长因子受体MET的胃癌细胞对选择性抑制剂PHA-665752非常敏感。虽然MET的激活主要与肿瘤细胞的迁移和侵袭性有关，但在这些细胞中扩增的野生型MET是结构性激活的，其持续的信号转导是细胞生存所必需的。在5个MET扩增的胃癌细胞系中，PHA-665752诱导了5个细胞的大量凋亡，而在12个未增加基因拷贝数的细胞系中，有0个细胞发生了大量的细胞凋亡(P=0.00016)。因此，MET扩增可以识别对这一途径的中断唯一敏感的上皮性癌症的子集，并确定适合于使用MET抑制剂进行靶向治疗的临床试验的患者组。
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.