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  • Title: A selective c-met inhibitor blocks an autocrine hepatocyte growth factor growth loop in ANBL-6 cells and prevents migration and adhesion of myeloma cells.
    Author: Hov H, Holt RU, Rø TB, Fagerli UM, Hjorth-Hansen H, Baykov V, Christensen JG, Waage A, Sundan A, Børset M.
    Journal: Clin Cancer Res; 2004 Oct 01; 10(19):6686-94. PubMed ID: 15475459.
    Abstract:
    PURPOSE: We wanted to examine the role of the hepatocyte growth factor (HGF) receptor c-Met in multiple myeloma by applying a novel selective small molecule tyrosine kinase inhibitor, PHA-665752, directed against the receptor. EXPERIMENTAL DESIGN: Four biological sequels of HGF related to multiple myeloma were studied: (1) proliferation of myeloma cells, (2) secretion of interleukin-11 from osteogenic cells, (3) migration of myeloma cells, and (4) adhesion of myeloma cells to fibronectin. We also examined effects of the c-Met inhibitor on intracellular signaling pathways in myeloma cells. RESULTS: PHA-665752 effectively blocked the biological responses to HGF in all assays, with 50% inhibition at 5 to 15 nmol/L concentration and complete inhibition at around 100 nmol/L. PHA-665752 inhibited phosphorylation of several tyrosine residues in c-Met (Tyr(1003), Tyr(1230/1234/1235), and Tyr(1349)), blocked HGF-mediated activation of Akt and p44/42 mitogen-activated protein kinase, and prevented the adaptor molecule Gab1 from complexing with c-Met. In the HGF-producing myeloma cell line ANBL-6, PHA-665752 revealed an autocrine HGF-c-Met-mediated growth loop. The inhibitor also blocked proliferation of purified primary myeloma cells, suggesting that autocrine HGF-c-Met-driven growth loops are important for progression of multiple myeloma. CONCLUSIONS: Collectively, these findings support the role of c-Met and HGF in the proliferation, migration, and adhesion of myeloma cells and identify c-Met kinase as a therapeutic target for treatment of patients with multiple myeloma.
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