Inhibition of the spindle assembly checkpoint kinase Mps-1 as a novel therapeutic strategy in malignant mesothelioma

Malignant mesothelioma (MM) is an aggressive malignancy, highly resistant to current medical and surgical therapies, whose tumor cells characteristically show a high level of aneuploidy and genomic instability. We tested our hypothesis that targeting chromosomal instability in MM would improve respo...

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Bibliographic Details
Published in:	Oncogene Vol. 36; no. 46; pp. 6501 - 6507
Main Authors:	Szymiczek, A, Carbone, M, Pastorino, S, Napolitano, A, Tanji, M, Minaai, M, Pagano, I, Mason, J M, Pass, H I, Bray, M R, Mak, T W, Yang, H
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 16-11-2017 Nature Publishing Group
Subjects:	631/67/1059 631/67/1641 Aneuploidy Animals Antineoplastic Agents - administration & dosage Antineoplastic Agents - therapeutic use Antineoplastic Combined Chemotherapy Protocols - therapeutic use Apoptosis Cancer Cancer therapies Care and treatment Cell Biology Cell Cycle Proteins - antagonists & inhibitors Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell division Cell fate Cell Line, Tumor Cell Survival - drug effects Cell Survival - genetics Chemotherapy Cisplatin Cisplatin - administration & dosage Development and progression Drug therapy Enzyme inhibitors Enzymes Gene Expression Regulation, Neoplastic - drug effects Genetic aspects Genomic instability Health aspects Human Genetics Humans Internal Medicine Kinases Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - metabolism M Phase Cell Cycle Checkpoints - drug effects M Phase Cell Cycle Checkpoints - genetics Malignancy Medicine Medicine & Public Health Mesothelioma Mesothelioma - drug therapy Mesothelioma - genetics Mesothelioma - metabolism Mesothelioma, Malignant Methods Mice, Inbred BALB C Mitosis Molecular targeted therapy Neoplasms, Experimental - drug therapy Neoplasms, Experimental - genetics Neoplasms, Experimental - metabolism Oncology Patient outcomes Patients Pemetrexed - administration & dosage Phosphotransferases Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - therapeutic use Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Protein-Tyrosine Kinases - antagonists & inhibitors Protein-Tyrosine Kinases - genetics Protein-Tyrosine Kinases - metabolism Pyrazoles - pharmacology Pyrimidines - pharmacology Regulation short-communication Survival Analysis Tumor cells United States
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Summary:	Malignant mesothelioma (MM) is an aggressive malignancy, highly resistant to current medical and surgical therapies, whose tumor cells characteristically show a high level of aneuploidy and genomic instability. We tested our hypothesis that targeting chromosomal instability in MM would improve response to therapy. Thr/Tyr kinase (TTK)/monopolar spindle 1 kinase (Mps-1) is a kinase of the spindle assembly checkpoint that controls cell division and cell fate. CFI-402257 is a novel, selective inhibitor of Mps-1 with antineoplastic activity. We found that CFI-402257 suppresses MM growth. We found that Mps-1 is overexpressed in MM and that its expression correlates with poor patients’ outcome. In vitro , CFI-402257-mediated inhibition of Mps-1 resulted in abrogation of the mitotic checkpoint, premature progression through mitosis, marked aneuploidy and mitotic catastrophe. In vivo , CFI-402257 reduced MM growth in an orthotopic, syngeneic model, when used as a single agent, and more so when used in combination with cisplatin+pemetrexed, the current standard of care. Our preclinical findings indicate that CFI-402257 is a promising novel therapeutic agent to improve the efficacy of the current chemotherapeutic regimens for MM patients.
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2017.266