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

ABSTRACT: GSK3alpha has been identified as a new target in the treatment of acute myeloid leukemia (AML). However, most GSK3 inhibitors lack specificity for GSK3alpha over GSK3beta and other kinases. We have previously shown in lung cancer cells that GSK3alpha and to a lesser extent GSK3beta 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 beta-catenin compared to the pan-GSK3 inhibitor LiCl. Subsequent drug combination studies identified the BCL-2 inhibitor ABT-199 to synergize with tivantinib. Interestingly, the addition of ABT-199 to tivantinib completely abrogated tivantinib induced beta-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 GSK3alpha/beta inhibitor that potently kills AML cells and tivantinib single agent or combination therapy with ABT-199 may represent attractive new therapeutic opportunities for AML.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Myeloid Cell

DISEASE(S): Acute Leukemia

SUBMITTER: John Koomen  

LAB HEAD: Uwe Rix, PhD

PROVIDER: PXD010217 | Pride | 2019-01-29

REPOSITORIES: Pride