title: T-LAK cell-originated protein kinase presents a novel therapeutic target in FLT3-ITD mutated acute myeloid leukemia.
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 IC50 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.
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: Houda
authors.initials: H
authors.lastname: Alachkar
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Mutonga
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Malnassy
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: Jae-Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: Noreen
authors.initials: N
authors.lastname: Fulton
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Woods
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Meng
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Kline
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: Gordana
authors.initials: G
authors.lastname: Raca
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: Olatoyosi
authors.initials: O
authors.lastname: Odenike
authors.affiliation: OncoTherapy Science, Inc., Kanagawa, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Takamatsu
authors.affiliation: OncoTherapy Science, Inc., Kanagawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyamoto
authors.affiliation: OncoTherapy Science, Inc., Kanagawa, Japan.
authors.forename: Yo
authors.initials: Y
authors.lastname: Matsuo
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Stock
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D058990:Molecular Targeted Therapy; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; C409022:PDZ-binding kinase
keywords: AML; CEBPA; FLT3-ITD; TOPK; kinase inhibitor