Small molecule c-met inhibitor pha665752: Effect on cell growth and motility in papillary thyroid carcinoma

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 phosphorylatlon, downstream signaling, hepatocyte growth factor (HGF)-dependent cell growth, and induction of apoptosis was studied. The IC50 of PHA665752 in c-met-expressing PTC cells was determined, and growth curves at 0.1 x, 1 x, and 10x IC50 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. (c) 2008 Wiley Periodicals, Inc.