title: Targeting the pro-survival protein MET with tivantinib (ARQ 197) inhibits growth of multiple myeloma cells.
abstract: The hepatocyte growth factor (HGF)/MNNG HOS transforming gene (MET) pathway regulates cell growth, survival, and migration. MET is mutated or amplified in several malignancies. In myeloma, MET is not mutated, but patients have high plasma concentrations of HGF, high levels of MET expression, and gene copy number, which are associated with poor prognosis and advanced disease. Our previous studies demonstrated that MET is critical for myeloma cell survival and its knockdown induces apoptosis. In our current study, we tested tivantinib (ARQ 197), a small-molecule pharmacological MET inhibitor. At clinically achievable concentrations, tivantinib induced apoptosis by >50% in all 12 human myeloma cell lines tested. This biologic response was associated with down-regulation of MET signaling and inhibition of the mitogen-activated protein kinase and phosphoinositide 3-kinase pathways, which are downstream of the HGF/MET axis. Tivantinib was equally effective in inducing apoptosis in myeloma cell lines resistant to standard chemotherapy (melphalan, dexamethasone, bortezomib, and lenalidomide) as well as in cells that were co-cultured with a protective bone marrow microenvironment or with exogenous cytokines. Tivantinib induced apoptosis in CD138+ plasma cells from patients and demonstrated efficacy in a myeloma xenograft mouse model. On the basis of these data, we initiated a clinical trial for relapsed/refractory multiple myeloma (MM). In conclusion, MET inhibitors may be an attractive target-based strategy for the treatment of MM.
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Shadia
authors: S
authors: Zaman
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Shujun
authors: S
authors: Shentu
authors: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Jing
authors: J
authors: Yang
authors: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Jin
authors: J
authors: He
authors: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Robert Z
authors: RZ
authors: Orlowski
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX, USA.
authors: Christine M
authors: CM
authors: Stellrecht
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX, USA; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: vgandhi@mdanderson.org.
authors: Varsha
authors: V
authors: Gandhi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000069286:Bortezomib / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000077269:Lenalidomide; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C551661:ARQ 197; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011760:Pyrrolidinones; D011804:Quinolines; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; D019859:Proto-Oncogene Proteins c-met; D000077269:Lenalidomide; D008558:Melphalan