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.

NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains

“…As shown in Fig. 2f, these changes are linked to the activation of oncogenes involved in multiple myeloma including SYK [43][44][45][46][47] , MET [48][49][50] and SH3GL3 51 in NSD2 overexpressing cells ( Fig. 2f).…”

Comprehensive review of targeted therapy for colorectal cancer

“…In vivo and in vitro experiments confirmed its ability to impair the growth of various cancers. [317][318][319] Tivantinib has been investigated as an independent drug or combined with sorafenib in phase II and III trials in patients with liver cancer and combined with erlotinib in phase III trials in patients with NSCLC. Data showed that patients with liver cancer with MET overexpression had a better OS than those without MET overexpression in a phase II trial, but the significance was lost in a phase III trial, while the use of tivantinib contributed little to the prognosis of NSCLC.…”

ARQ-197, a small-molecule inhibitor of c-Met, reduces tumour burden and prevents myeloma-induced bone disease in vivo

“…ARQ-197 is a selective inhibitor of c-Met activity, and is found to be non-ATP competitive, therefore retaining its effectiveness in cells [ 44 ]. The efficacy of this SMI has been tested on a number of human cancer cell lines, including MM [ 30 , 45 – 46 ]. ARQ-197 has also been tested in clinical studies on numerous types of tumour including MM [ 47 – 48 ].…”

“…SU11274 inhibited myeloma cell proliferation and migration in vitro [ 25 , 29 ]. ARQ-197 (Tivantinib), a non-ATP-competitive c-Met inhibitor, induced apoptosis by >50% in 12 human myeloma cell lines, including those resistant to standard chemotherapy, and in a murine xenograft model of MM it was shown to reduce a subcutaneous tumour [ 30 ]. To date the effects of ARQ-197 on myeloma induced-bone disease have not been investigated.…”