Ma Patrick C, Schaefer Erik, Christensen James G, Salgia Ravi
Section of Hematology/Oncology, Department of Medicine, Pritzker School of Medicine, University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
Clin Cancer Res. 2005 Mar 15;11(6):2312-9. doi: 10.1158/1078-0432.CCR-04-1708.
c-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.
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 TPR-MET-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.
PHA665752 specifically inhibited cell growth in BaF3. TPR-MET cells (IC(50) < 0.06 micromol/L), induced apoptosis and cell cycle arrest. Constitutive cell motility and migration of the BaF3. TPR-MET cells was 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.
PHA665752 is a potent small molecule-selective c-MET inhibitor and is highly active against TPR-MET-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.
c-MET被认为是分子治疗抑制的一个有吸引力的受体靶点。TPR-MET是MET的一种组成型活性致癌变体，是测试c-MET抑制剂的理想模型。在此，我们对一种小分子c-MET抑制剂PHA665752进行了特性分析，并测试了其与雷帕霉素抑制剂的哺乳动物靶点的协同作用，作为潜在的靶向治疗。
确定PHA665752处理对TPR-MET转化细胞的细胞生长、运动性和迁移、凋亡及细胞周期停滞的影响。此外，还确定了PHA665752对MET磷酸化及其下游效应分子p-AKT和p-S6K的影响。最后，在PHA665752和雷帕霉素存在的情况下测试TPR-MET转化细胞的生长。还对H441非小细胞肺癌（NSCLC）细胞（c-Met激活）进行了PHA665752和雷帕霉素测试。
PHA665752特异性抑制BaF3.TPR-MET细胞的生长（IC(50)<0.06微摩尔/升），诱导凋亡和细胞周期停滞。BaF3.TPR-MET细胞的组成型细胞运动性和迁移也受到抑制。PHA665752抑制TPR-MET的特异性磷酸化以及雷帕霉素哺乳动物靶点途径下游靶点的磷酸化。与PHA665752联合使用时，雷帕霉素显示出协同抑制作用，可降低BaF3.TPR-MET和表达c-MET的H441 NSCLC细胞的生长。
PHA665752是一种有效的小分子选择性c-MET抑制剂，在生物学和生物化学方面对TPR-MET转化细胞具有高活性。PHA665752对H441 NSCLC细胞也有活性。c-MET抑制剂可与雷帕霉素协同治疗NSCLC，对这种联合治疗c-MET表达癌症的体内研究值得开展。
