Potent anti-myeloma activity of the TOPK inhibitor OTS514 in pre-clinical models.

Abstract

Multiple myeloma (MM) continues to be considered incurable, necessitating new drug discovery. The mitotic kinase T-LAK cell-originated protein kinase/PDZ-binding kinase (TOPK/PBK) is associated with proliferation of tumor cells, maintenance of cancer stem cells, and poor patient prognosis in many cancers. In this report, we demonstrate potent anti-myeloma effects of the TOPK inhibitor OTS514 for the first time. OTS514 induces cell cycle arrest and apoptosis at nanomolar concentrations in a series of human myeloma cell lines (HMCL) and prevents outgrowth of a putative CD138+ stem cell population from MM patient-derived peripheral blood mononuclear cells. In bone marrow cells from MM patients, OTS514 treatment exhibited preferential killing of the malignant CD138+ plasma cells compared with the CD138- compartment. In an aggressive mouse xenograft model, OTS964 given orally at 100 mg/kg 5 days per week was well tolerated and reduced tumor size by 48%-81% compared to control depending on the initial graft size. FOXO3 and its transcriptional targets CDKN1A (p21) and CDKN1B (p27) were elevated and apoptosis was induced with OTS514 treatment of HMCLs. TOPK inhibition also induced loss of FOXM1 and disrupted AKT, p38 MAPK, and NF-κB signaling. The effects of OTS514 were independent of p53 mutation or deletion status. Combination treatment of HMCLs with OTS514 and lenalidomide produced synergistic effects, providing a rationale for the evaluation of TOPK inhibition in existing myeloma treatment regimens.

• Authors: Andrew T Stefka, David Johnson, Shaun Rosebeck, Jae-Hyun Park, Yusuke Nakamura, Andrzej J Jakubowiak
• Journal: Cancer medicine (Cancer Med) Vol. 9 Issue 1 Pg. 324-334 (01 2020) ISSN: 2045-7634 [Electronic] United States
• PMID: 31714026 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• OTS514
• Protein Kinase Inhibitors
• Quinolones
• Thiophenes
• Mitogen-Activated Protein Kinase Kinases
• PDZ-binding kinase
• Lenalidomide

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Drug Synergism
• Female
• Humans
• Lenalidomide (pharmacology, therapeutic use)
• Leukocytes, Mononuclear
• Mice
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
• Multiple Myeloma (blood, drug therapy, pathology)
• Primary Cell Culture
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Quinolones (pharmacology, therapeutic use)
• Thiophenes (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays