Targeting the Pro-Survival Protein MET with Tivantinib (ARQ 197) Inhibits Growth of Multiple Myeloma Cells

Shadia Zaman, Shujun Shentu, Jing Yang, Jin He, Robert Z. Orlowski, Christine M. Stellrecht, Varsha Gandhi

Research output: Contribution to journalArticle

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)289-300
Number of pages12
JournalNeoplasia (United States)
Volume17
Issue number3
DOIs
StatePublished - Mar 1 2015

ASJC Scopus subject areas

  • Cancer Research

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