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  • Title: Small molecule c-MET inhibitor PHA665752: effect on cell growth and motility in papillary thyroid carcinoma.
    Author: Chattopadhyay C, El-Naggar AK, Williams MD, Clayman GL.
    Journal: Head Neck; 2008 Aug; 30(8):991-1000. PubMed ID: 18327775.
    Abstract:
    BACKGROUND: c-Met is upregulated in papillary thyroid carcinoma (PTC) and can be an attractive therapeutic target. We tested the effects of the small molecule c-met inhibitor PHA665752 in blocking c-met-dependent phenotypic effects in PTC cell lines. METHODS: PTC patient tissues and cell lines were evaluated for c-met expression. The effect of PHA665752 on c-met phosphorylation, downstream signaling, hepatocyte growth factor (HGF)-dependent cell growth, and induction of apoptosis was studied. The IC(50) of PHA665752 in c-met-expressing PTC cells was determined, and growth curves at 0.1x, 1x, and 10x IC(50) concentrations were obtained. Poly(ADP-ribose) polymerase (PARP) and caspase-9-processing post-PHA665752 treatment were studied as markers of apoptosis, and assays analyzing HGF-dependent cell invasion and migration in the presence and absence of PHA665752 were done. RESULTS: c-Met was upregulated in most of the patient tissues with PTC and in many PTC cell lines. PHA665752 specifically inhibited c-met phosphorylation, c-met-dependent cell growth, signal transduction, cell survival, cell invasion, and migration in PTC cells with high c-met. CONCLUSIONS: PHA665752 is an effective and specific inhibitor of c-met in PTC cells with high levels of c-met expression.
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