Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia

Sci Rep. 2019 Jan 24;9(1):606. doi: 10.1038/s41598-018-37174-6.


GSK3α has been identified as a new target in the treatment of acute myeloid leukemia (AML). However, most GSK3 inhibitors lack specificity for GSK3α over GSK3β and other kinases. We have previously shown in lung cancer cells that GSK3α and to a lesser extent GSK3β are inhibited by the advanced clinical candidate tivantinib (ARQ197), which was designed as a MET inhibitor. Thus, we hypothesized that tivantinib would be an effective therapy for the treatment of AML. Here, we show that tivantinib has potent anticancer activity across several AML cell lines and primary patient cells. Tivantinib strongly induced apoptosis, differentiation and G2/M cell cycle arrest and caused less undesirable stabilization of β-catenin compared to the pan-GSK3 inhibitor LiCl. Subsequent drug combination studies identified the BCL-2 inhibitor ABT-199 to synergize with tivantinib while cytarabine combination with tivantinib was antagonistic. Interestingly, the addition of ABT-199 to tivantinib completely abrogated tivantinib induced β-catenin stabilization. Tivantinib alone, or in combination with ABT-199, downregulated anti-apoptotic MCL-1 and BCL-XL levels, which likely contribute to the observed synergy. Importantly, tivantinib as single agent or in combination with ABT-199 significantly inhibited the colony forming capacity of primary patient AML bone marrow mononuclear cells. In summary, tivantinib is a novel GSK3α/β inhibitor that potently kills AML cells and tivantinib single agent or combination therapy with ABT-199 may represent attractive new therapeutic opportunities for AML.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
  • Down-Regulation / drug effects
  • Drug Repositioning*
  • Drug Synergism
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism
  • HL-60 Cells
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / pathology
  • Lithium Chloride / pharmacology
  • Lithium Chloride / therapeutic use
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Proto-Oncogene Proteins c-met / metabolism
  • Pyrrolidinones / pharmacology*
  • Pyrrolidinones / therapeutic use
  • Quinolines / pharmacology*
  • Quinolines / therapeutic use
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism


  • ARQ 197
  • Bridged Bicyclo Compounds, Heterocyclic
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Protein Kinase Inhibitors
  • Pyrrolidinones
  • Quinolines
  • Sulfonamides
  • bcl-X Protein
  • Proto-Oncogene Proteins c-met
  • Glycogen Synthase Kinase 3
  • glycogen synthase kinase 3 alpha
  • Lithium Chloride
  • venetoclax