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A Selective Small Molecule c-MET Inhibitor, PHA665752, Cooperates with Rapamycin

¹ Section of Hematology/Oncology, Department of Medicine, Pritzker School of Medicine, University of Chicago Medical Center, Chicago, Illinois; ² BioSource International, Inc., Camarillo, California; and ³ Research Pharmacology, Pfizer, Inc., La Jolla, California

Requests for reprints: Ravi Salgia, Section of Hematology/Oncology, Department of Medicine, Room M-255A, University of Chicago Medical Center, 5841 South Maryland Avenue, MC2115, Chicago, IL, 60637. Phone: 773-702-4399; Fax: 773-834-1798; E-mail: rsalgia{at}medicine.bsd.uchicago.edu.

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 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.

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.

Key Words: c-MET • HGF • kinase inhibitor • phosphorylation • tumor

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