title: Targeting MET kinase with the small-molecule inhibitor amuvatinib induces cytotoxicity in primary myeloma cells and cell lines.
abstract: BACKGROUND
  MET is a receptor tyrosine kinase that is activated by the ligand HGF and this pathway promotes cell survival, migration, and motility. In accordance with its oncogenic role, MET is constitutively active, mutated, or over-expressed in many cancers. Corollary to its impact, inhibition of MET kinase activity causes reduction of the downstream signaling and demise of cells. In myeloma, a B-cell plasma malignancy, MET is neither mutated nor over-expressed, however, HGF is increased in plasma or serum obtained from myeloma patients and this was associated with poor prognosis. The small-molecule, amuvatinib, inhibits MET receptor tyrosine kinase. Based on this background, we hypothesized that targeting the HGF/MET signaling pathway is a rational approach to myeloma therapy and that myeloma cells would be sensitive to amuvatinib.
  
  
  METHODS
  Expression of MET and HGF mRNAs in normal versus malignant plasma cells was compared during disease progression. Cell death and growth as well as MET signaling pathway were assessed in amuvatinib treated primary myeloma cells and cell lines.
  
  
  RESULTS
  There was a progressive increase in the transcript levels of HGF (but not MET) from normal plasma cells to refractory malignant plasma cells. Amuvatinib readily inhibited MET phosphorylation in primary CD138+ cells from myeloma patients and in concordance, increased cell death. A 48-hr amuvatinib treatment in high HGF-expressing myeloma cell line, U266, resulted in growth inhibition. Levels of cytotoxicity were time-dependent; at 24, 48, and 72 h, amuvatinib (25 μM) resulted in 28%, 40%, and 55% cell death. Consistent with these data, there was an amuvatinib-mediated decrease in MET phosphorylation in the cell line. Amuvatinib at concentrations of 5, 10, or 25 μM readily inhibited HGF-dependent MET, AKT, ERK and GSK-3-beta phosphorylation. MET-mediated effects were not observed in myeloma cell line that has low MET and/or HGF expression.
  
  
  CONCLUSIONS
  These data suggest that at the cellular level MET/HGF pathway inclines with myeloma disease progression. Amuvatinib, a small molecule MET kinase inhibitor, is effective in inducing growth inhibition and cell death in myeloma cell lines as well as primary malignant plasma cells. These cytostatic and cytotoxic effects were associated with an impact on MET/HGF pathway.
authors: Cornel Joseph
authors: CJ
authors: Phillip
authors: Shadia
authors: S
authors: Zaman
authors: Shujun
authors: S
authors: Shentu
authors: Kumudha
authors: K
authors: Balakrishnan
authors: Jiexin
authors: J
authors: Zhang
authors: Veera
authors: V
authors: Baladandayuthapani
authors: Pietro
authors: P
authors: Taverna
authors: Sanjeev
authors: S
authors: Redkar
authors: Michael
authors: M
authors: Wang
authors: Christine Marie
authors: CM
authors: Stellrecht
authors: Departments of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. vgandhi@mdanderson.org.
authors: Varsha
authors: V
authors: Gandhi
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010879:Piperazines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013890:Thiourea
chemical_list: D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D013890:Thiourea; C521047:amuvatinib