A selective small molecule c-MET inhibitor, PHA665752, cooperates with rapamycin
A selective small molecule c-MET inhibitor, PHA665752, cooperates with rapamycin
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DOI：
10.1158/1078-0432.ccr-04-1708
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发表时间：
2005-03-15
影响因子：
11.5
通讯作者：
Salgia, R
中科院分区：
文献类型：
--
作者：
Ma, PC;Schaefer, E;Salgia, R
目的：e-MET被认为是分子治疗抑制的有吸引力的受体靶点。TPR-MET是MET的组成型活性致癌变体，是检测c-MET抑制剂的极佳模型。在这里，我们的特点是一个小分子c-MET抑制剂，PHA 665752，并测试其合作与哺乳动物的雷帕霉素抑制剂作为潜在的靶向therapeutic.Experimental Design：PHA 665752治疗的效果，确定对细胞生长，运动和迁移，凋亡，细胞周期阻滞的TPR-MET转化细胞。此外，还测定了PHA 665752对MET及其下游效应物p-AKT和p-S6 K的磷酸化的影响。最后，在PHA 665752和雷帕霉素存在下测试TPRMET转化的细胞的生长。结果：PHA 665752特异性抑制BaF 3.TPR-MET细胞的生长（IC 50 < 0.06 μ mol/L），诱导细胞凋亡和细胞周期阻滞。TPR-MET细胞的组成性运动和迁移也受到抑制。PHA 665752抑制TPR-MET的特异性磷酸化以及雷帕霉素途径哺乳动物靶标的下游靶标的磷酸化。结论：PHA 665752是一种有效的小分子选择性c-MET抑制剂，对TPRMET转化的H441 NSCLC细胞具有良好的生物学和生化活性。PHA 665752对H441 NSCLC细胞也有活性。c-MET抑制剂可以与雷帕霉素协同治疗NSCLC，并且这种组合对表达c-MET的癌症的体内研究将是值得的。
Purpose: e-MET is believed to be an attractive receptor target for molecular therapeutic inhibition. TPR-MET, a constitutively active oncogenic variant of MET, serves as excellent model for testing c-MET inhibitors. Here, we characterized a small molecule c-MET inhibitor, PHA665752, and tested its cooperation with the mammalian target of rapamycin inhibitor as potential targeted therapy.Experimental Design: The effect of PHA665752 treatment was determined on cell growth, motility and migration, apoptosis, and cell-cycle arrest of TPR-MET-transformed cells. Moreover, the effect of PHA665752 on the phosphorylation on MET, as well as its downstream effectors, p-AKT and p-S6K, was also determined. Finally, growth of TPRMET-transformed cells was tested in the presence of PHA665752 and rapamycin. H441 non-small cell lung cancer (NSCLC) cells (with activated c-Met) were also tested against both PHA665752 and rapamycin.Results: PRA665752 specifically inhibited cell growth in BaF3.TPR-MET cells (IC50 < 0.06 mu mol/L), induced apoptosis and cell cycle arrest. Constitutive cell motility and migration of the BaF3.TPR-MET cells were also inhibited. PHA665752 inhibited specific phosphorylation of TPR-MET as well as phosphorylation of downstream targets of the mammalian target of rapamycin pathway. When combined with PHA665752, rapamycin showed cooperative inhibition to reduce growth of BaF3.TPR-MET- and c-MET-expressing H441 NSCLC cells.Conclusions: PHA665752 is a potent small molecule-selective c-MET inhibitor and is highly active against TPRMET-transformed cells both biologically and biochemically. PHA665752 is also active against H441 NSCLC cells. The c-MET inhibitor can cooperate with rapamycin in therapeutic inhibition of NSCLC, and in vivo studies of this combination against c-MET expressing cancers would be merited.