Off-Target Based Drug Repurposing Opportunities For Tivantinib In Acute Myeloid Leukemia

GSK3 alpha has been shown to be a new target in the treatment of acute myeloid leukemia (AML); however current GSK3 inhibitors are unselective and target both GSK3 alpha and GSK3 beta. Interestingly, a known pan-GSK3 inhibitor LiCl has been previously investigated for the treatment of AML yet has met limited clinical success. This could be partly due to the fact that pan-GSK3 inhibition results in beta-catenin stabilization, which has been shown to mediate hematopoietic self-renewal and leukemogenesis. As beta-catenin stabilization requires inhibition of both kinases and most GSK3 inhibitors target GSK3 alpha and GSK3 beta with equal potency, these compounds may possess some significant limitations. We have previously shown GSK3 alpha to be a prominent target of the intended MET inhibitor tivantinib (ARQ197) and that tivantinib shows some specificity for GSK3 alpha over GSK3 beta. We thus hypothesized that tivantinib would be an effective therapy for the treatment of AML. Consistently, tivantinib potently inhibited cellular viability across several AML cell lines. Using an unbiased, mass-spectrometry based chemical proteomics approach; we confirmed GSK3 alpha (and to a slightly lesser extent GSK3 beta) to be targeted by tivantinib in AML. Tivantinib strongly induced apoptosis as compared to the pan-GSK3 inhibitor LiCl in these cells while LiCl showed larger effects on cell differentiation. Interestingly tivantinib caused less stabilization of beta-catenin as compared to LiCl. Subsequent drug combination studies identified the Bcl-2 inhibitor ABT-199 to synergize with tivantinib and to amplify apoptosis as seen by PARP1 cleavage. Furthermore, the combination of tivantinib with ABT-199 completely abrogated beta-catenin stabilization. Tivantinib was able to significantly inhibit colony formation of primary AML patient bone marrow mononuclear cells (BMNCs) and ABT-199 combination showed significant benefit over tivantinib or ABT-199 alone. In summary, tivantinib has potent anticancer activity in AML based on targeting GSK3 alpha; and tivantinib single agent or combination with ABT-199 may represent a novel and exciting opportunity for the treatment of AML. Citation Format: Brent M. Kuenzi, Lily L. Remsing Rix, Sateesh S. Kunigal, Fumi Kinose, Claire E. Knezevic, Gabriela Wright, Jodi L. Kroeger, Jeffrey E. Lancet, Eric Padron, Uwe Rix. Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 675. doi:10.1158/1538-7445.AM2015-675