T-LAK cell-originated protein kinase presents a novel therapeutic target inFLT3-ITD mutated acute myeloid leukemia

// Houda Alachkar 1 , Martin Mutonga 1 , Gregory Malnassy 1 , Jae-Hyun Park 1 , Noreen Fulton 1 , Alex Woods 1 , Liping Meng 1 , Justin Kline 1 , Gordana Raca 1 , Olatoyosi Odenike 1 , Naofumi Takamatsu 2 , Takashi Miyamoto 2 , Yo Matsuo 2 , Wendy Stock 1 , Yusuke Nakamura 1 1 Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA 2 OncoTherapy Science, Inc., Kanagawa, Japan Correspondence to: Yusuke Nakamura, e-mail: ynakamura@bsd.uchicago.edu Keywords: AML, FLT3-ITD, TOPK, CEBPA, kinase inhibitor Received: July 08, 2015      Accepted: September 22, 2015      Published: October 02, 2015 ABSTRACT Gain-of-function mutations of FLT3 ( FLT3 -ITD), comprises up to 30% of normal karyotype acute myeloid leukemia (AML) and is associated with an adverse prognosis. Current FLT3 kinase inhibitors have been tested extensively, but have not yet resulted in a survival benefit and novel therapies are awaited. Here we show that T-LAK cell-originated protein kinase (TOPK), a mitotic kinase highly expressed in and correlated with more aggressive phenotype in several types of cancer, is expressed in AML but not in normal CD34+ cells and that TOPK knockdown decreased cell viability and induced apoptosis. Treatment of AML cells with TOPK inhibitor (OTS514) resulted in a dose-dependent decrease in cell viability with lower IC 50 in FLT3 -mutated cells, including blasts obtained from patients relapsed after FLT3-inhibitor treatment. Using a MV4-11-engrafted mouse model, we found that mice treated with 7.5 mg/kg IV daily for 3 weeks survived significantly longer than vehicle treated mice (median survival 46 vs 29 days, P < 0.001). Importantly, we identified TOPK as a FLT3 -ITD and CEBPA regulated kinase, and that modulating TOPK expression or activity resulted in significant decrease of FLT3 expression and CEBPA phosphorylation. Thus, targeting TOPK in FLT3 -ITD AML represents a novel therapeutic approach for this adverse risk subset of AML.