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TTK/MPS1 inhibitor OSU-13 targets the mitotic checkpoint and is a potential therapeutic strategy for myeloma.

Authors
  • Longo, Larissa Valle Guilhen1
  • Hughes, Tiffany1
  • McNeil-Laidley, Betina1
  • Cottini, Francesca1
  • Hilinski, Gerard2
  • Merritt, Elizabeth3
  • Benson, Don M4
  • 1 Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA; Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, Columbus, OH.
  • 2 Drug Development Institute, Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, Columbus, OH.
  • 3 Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, Columbus, OH.
  • 4 Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA; Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, Columbus, OH. [email protected].
Type
Published Article
Journal
Haematologica
Publisher
Ferrata Storti Foundation
Publication Date
Feb 01, 2024
Volume
109
Issue
2
Pages
578–590
Identifiers
DOI: 10.3324/haematol.2023.282838
PMID: 37496433
Source
Medline
Language
English
License
Unknown

Abstract

Despite substantial recent advances in treatment, multiple myeloma (MM) remains an incurable disease, with a shortage of treatment options for patients with high-risk disease, warranting the need for novel therapeutic targets and treatment approaches. Threonine and tyrosine kinase (TTK), also known as monopolar spindle 1 (MPS1), is a kinase essential for the mitotic spindle checkpoint whose expression correlates to unfavorable prognosis in several cancers. Here, we report the importance of TTK in MM, and the effects of the TTK inhibitor OSU-13. Elevated TTK expression correlated with amplification/ gain of 1q21 and decreased overall and event-free survival in MM. Treatment with OSU-13 inhibited TTK activity efficiently and selectively at a similar concentration range to other TTK inhibitor clinical candidates. OSU-13 reduced proliferation and viability of primary human MM cells and cell lines, especially those with high 1q21 copy numbers, and triggered apoptosis through caspase 3 and 7 activation. In addition, OSU-13 induced DNA damage and severe defects in chromosome alignment and segregation, generating aneuploidy. In vivo, OSU-13 decreased tumor growth in mice with NCI-H929 xenografts. Collectively, our findings reveal that inhibiting TTK with OSU-13 is a potential therapeutic strategy for MM, particularly for a subset of high-risk patients with poor outcome.

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