A selective small molecule c-MET inhibitor, PHA665752, cooperates with rapamycin

Patrick C. Ma, Erik Schaefer, James G. Christensen, Ravi Salgia

Research output: Contribution to journalArticlepeer-review

123 Scopus citations


Purpose: 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. 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 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. Results: PHA665752 specifically inhibited cell growth in BaF3.TPR-MET cells (IC50 < 0.06 μmol/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 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.

Original languageEnglish (US)
Pages (from-to)2312-2319
Number of pages8
JournalClinical Cancer Research
Issue number6
StatePublished - Mar 15 2005

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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