A Selective Inhibitor of c-Met Blocks an Autocrine HGF Growth Loop in ANBL-6 Cells and Prevents Migration and Adhesion of Myeloma Cells

• Published in: Blood Vol. 104; no. 11; p. 2358
• Main Authors: Borset, Magne, Hov, Hakon, Holt, Randi U., Ro, Torstein B., Fagerli, Unn-Merete, Hjorth-Hansen, Henrik, Baykov, Vadim, Christensen, James G., Waage, Anders, Sundan, Anders
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 16.11.2004
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V104.11.2358.2358

We examined 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. 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. PHA-665752 effectively blocked the biological responses to HGF in all assays, with 50 % inhibition at 5-15 nM concentration and complete inhibition at around 100 nM. PHA-665752 inhibited phosphorylation of several tyrosine residues in c-Met (Y1003, Y1230/1234/1235, and Y1349), blocked HGF-mediated activation of Akt and p44/42 Mitogen-activated protein kinase (MAPK), 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.