T-LAK cell-originated protein kinase presents a novel therapeutic target inFLT3-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.

T-LAK Cell-Originated Protein Kinase (TOPK) as a Prognostic Factor and a Potential Therapeutic Target in Ovarian Cancer

“…We recently reported that liposomal formulation of OTS964 could achieve complete regression of tumors in the human lung cancer xenograft model (15) and that treatment with OTS514 significantly elongated overall survival in murine engraft model of acute myeloid leukemia (16).…”

TOPK (T‐LAK cell‐originated protein kinase) inhibitor exhibits growth suppressive effect on small cell lung cancer

“…T‐lymphokine‐activated killer cell–originated protein kinase (TOPK), also known as PBK or PDZ‐binding kinase, is a Ser/Thr protein kinase that is highly expressed in a wide range of human malignancies, including acute myeloid leukemia (AML), breast cancer, Ewing sarcoma, kidney cancer and colorectal cancer . However, in normal adult tissues, TOPK expression is limited to the testis where it plays a key role in spermatogenesis .…”

“…Our efforts in this line of drug development identified two small molecular compounds, OTS514 and its derivative OTS964, as potent TOPK inhibitors . Treatment with TOPK inhibitors inhibited cytokinesis and effectively suppressed growth of cancer cells, and induced complete tumor regression in xenograft models of human lung cancer …”

“…T -lymphokine-activated killer cell-originated protein kinase (TOPK), also known as PBK or PDZ-binding kinase, is a Ser/Thr protein kinase that is highly expressed in a wide range of human malignancies, including acute myeloid leukemia (AML), breast cancer, Ewing sarcoma, kidney cancer and colorectal cancer. (1)(2)(3)(4)(5)(6)(7) However, in normal adult tissues, TOPK expression is limited to the testis where it plays a key role in spermatogenesis. (8) We and others reported that TOPK is essential in the cancer cell mitosis, (1,9,10) much highly expressed in cancer stem cells (CSC)-enriched tumor cell population, and associated with poor prognosis of multiple types of cancer.…”

“…(12,13) Our efforts in this line of drug development identified two small molecular compounds, OTS514 and its derivative OTS964, as potent TOPK inhibitors. (14) Treatment with TOPK inhibitors inhibited cytokinesis and effectively suppressed growth of cancer cells, (6,7) and induced complete tumor regression in xenograft models of human lung cancer. (14) Small cell lung cancer (SCLC) is a subtype of lung cancer that affects more than 200 000 people worldwide every year with a very high mortality rate, <15% of 2-year survival.…”