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

Brent M Kuenzi,Fumi Kinose,Jeffrey E Lancet,Uwe Rix,Eric Padron,Jodi L Kroeger,Lily L Remsing Rix

doi:10.1038/s41598-018-37174-6

Brent M Kuenzi, Fumi Kinose + Show 5 more

Open Access

https://doi.org/10.1038/s41598-018-37174-6

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Abstract

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.

Highlights

Despite significant advances in targeted therapy development and a growing repertoire of drugs being tested in the treatment of acute myeloid leukemia (AML)[1], patient outcomes for AML have changed little in the last several decades
Supporting this report, analysis of publically available expression levels of GSK3α and GSK3β using the BloodSpot database revealed that GSK3α is overexpressed across multiple AML subtypes as compared to normal hematopoietic lineages (Fig. S1a)
Consistent with GSK3α being overexpressed in AML, this analysis suggested that AML cell lines are significantly more sensitive to GSK3α silencing as compared to GSK3β gene silencing (Fig. S1c)

Summary

Introduction

Despite significant advances in targeted therapy development and a growing repertoire of drugs being tested in the treatment of acute myeloid leukemia (AML)[1], patient outcomes for AML have changed little in the last several decades. The 5-year overall survival rates of the majority of AML cases ranges from 5–15% in older patients to 30% in young adults[4] This lack of improvement in patient survival rates is primarily attributed to the limited efficacy of currently available therapies in AML and the need for new targeted drugs. There are a number of GSK3 inhibitors in development, but current compounds are either highly unselective featuring various off-targets in addition to GSK3α/β, lack isoform selectivity or have not yet advanced to clinical studies[11,12]. We have previously identified GSK3α/β as novel targets of tivantinib (ARQ197)[13], an advanced clinical drug candidate, which was initially thought to be a highly specific MET inhibitor[14]. The results presented suggest that tivantinib, either as a single agent or in combination with ABT-199, may be a novel and attractive targeted therapy option for AML

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