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Small molecule c-MET inhibitor PHA665752: effect on cell growth and motility in papillary thyroid carcinoma
Chandrani Chattopadhyay1, Adel K El-Naggar, Michelle D Williams
1Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
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.
Insights
The small molecule c-met inhibitor PHA665752 effectively blocks papillary thyroid carcinoma (PTC) cell growth and invasion. This study shows PHA665752 is a promising targeted therapy for PTC with high c-Met expression.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- c-Met receptor tyrosine kinase is frequently overexpressed in papillary thyroid carcinoma (PTC).
- Upregulated c-Met signaling drives tumor growth, survival, and metastasis in PTC, presenting a potential therapeutic target.
Purpose of the Study:
- To evaluate the efficacy of PHA665752, a small molecule inhibitor of c-Met, in preclinical PTC models.
- To investigate the impact of PHA665752 on c-Met phosphorylation, downstream signaling, and phenotypic characteristics of PTC cells.
Main Methods:
- Assessed c-Met expression in PTC patient tissues and cell lines.
- Determined the inhibitory concentration (IC50) of PHA665752 in PTC cells.
- Analyzed the effects of PHA665752 on c-Met phosphorylation, cell growth, apoptosis (PARP and caspase-9 processing), invasion, and migration.
Main Results:
- c-Met was found to be upregulated in a majority of PTC patient tissues and cell lines.
- PHA665752 demonstrated specific inhibition of c-Met phosphorylation and downstream signaling.
- PHA665752 significantly reduced HGF-dependent cell growth, survival, invasion, and migration in PTC cells with high c-Met expression.
Conclusions:
- PHA665752 is a potent and specific inhibitor of c-Met activity in PTC cells.
- The findings support PHA665752 as a potential targeted therapeutic agent for papillary thyroid carcinoma, particularly in tumors with high c-Met expression.
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