c-Met Is a Potentially New Therapeutic Target for Treatment of Human Melanoma

Abstract

Purpose: c-Met is a receptor tyrosine kinase involved in cell growth, invasion, metastases, and angiogenesis. In this study, we investigated the role of c-Met in melanoma biology using a novel small-molecule tyrosine kinase inhibitor SU11274 and small interfering (si) RNA against the receptor. Experimental Design: The effects of SU11274 and c-Met siRNA were studied on proliferation, apoptosis, differentiation, reactive oxygen species, and intracellular signaling. c-Met mutations were examined, and the expression of c-Met and activated c-Met was studied in nevi, primary, and metastatic melanoma. Results: c-Met was expressed in 6:7 melanoma cell lines by immunoblotting. SU11274 inhibited cell growth in all melanoma cell lines by 85% to 98% with an IC 50 between 1and 2.5 Amol/L and caused apoptosis (12-58%) in five out of six cell lines. siRNA against c-Met inhibited proliferation of melanoma cells by 60%. This is the first study that shows that SU11274 and siRNA induced microphthalmia-associated transcription factor (MITF) and several other melanoma differentiation proteins and a morphologically differentiated phenotype. SU11274 also inhibited reactive oxygen species formation and phosphorylation of c-Met receptor, AKT and S-6 kinase by the hepatocyte growth factor. A new missense c-Met mutation N948S was identified in cell lines and R988C in tumor tissue in the juxtamembrane domain of c-Met. It was found that c-Met was expressed in 88% of melanomas and 15% of nevi, and that c-Met (pY1003) was activated in 21% of human melanomas. Conclusion: These results support the role of c-Met in proliferation, apoptosis, differentiation, and tumor progression of melanoma. SU11274 could be used in the therapeutic inhibition of melanoma.

Differential 18F-FDG and 3′-Deoxy-3′-18F-Fluorothymidine PET Responses to Pharmacologic Inhibition of the c-MET Receptor in Preclinical Tumor Models

“…This response most likely reflects the arrest of a large proportion of cells in the G1 phase of the cell cycle, where 18 F-FLT uptake is minimal because of the low expression of thymidine kinase 1, the key rate-limiting enzyme in the cellular uptake and retention of 18 F-FLT. Further, this is consistent with the reduced Ki-67 staining in GTL-16 tumors observed in our previous crizotinib study (17) and the G1 cell cycle arrest observed with other MET inhibitors (30,31). These findings therefore demonstrate the potential utility of 18 F-FLT PET to monitor early tumor response to c-MET inhibition and provide a rationale for its evaluation in the clinical development of these inhibitors.…”

Cancer cells harboring MET gene amplification activate alternative signaling pathways to escape MET inhibition but remain sensitive to Hsp90 inhibitors

“…3 These data suggest that MET gene amplification may identify a subset of tumors addicted to c-Met-driven signaling and therefore sensitive to c-Met inhibitors. 5,6 Protein tyrosine kinases such as c-Met have been shown to be novel targets for molecular cancer therapy, and tyrosine kinase inhibitors (TKIs) represent a promising treatment modality. However, no matter the targeted kinase or the TKI used, patients who initially respond to such therapy eventually develop resistance.…”

Hydrocortisone Inhibits Cellular Proliferation by Downregulating Hepatocyte Growth Factor Synthesis in Human Osteoblasts

“…To elicidate the involvement of the autocrine/paracrine system for HGF in osteoblastic cell proliferation, we examined the effect of SU11274, a novel small-molecule tyrosine kinase inhibitor, on osteoblastic cell proliferation. At the IC 50 concentration for cell growth in human melanoma cell lines, 26) SU11274 significantly inhibited SaM-1 cell proliferation, probably because of high endogenous secretion of HGF; however, it did not inhibit the proliferation of HOS cells. These findings suggest that the inhibition of cellular proliferation by hydrocortisone is based upon interruption of the autocrine/paracrine loop via the downregulation of HGF synthesis in human osteoblasts, which produced a sufficient amount of HGF protein under control conditions.…”