Abstract
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.
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / therapeutic use*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / genetics
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Cisplatin / administration & dosage
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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M Phase Cell Cycle Checkpoints / drug effects
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M Phase Cell Cycle Checkpoints / genetics
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Mesothelioma / drug therapy*
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Mesothelioma / genetics
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Mesothelioma / metabolism
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Mesothelioma, Malignant
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Mice, Inbred BALB C
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / genetics
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Neoplasms, Experimental / metabolism
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Pemetrexed / administration & dosage
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / therapeutic use*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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Pyrazoles / pharmacology*
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Pyrimidines / pharmacology*
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Survival Analysis
Substances
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Antineoplastic Agents
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CFI-402257
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Cell Cycle Proteins
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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Pemetrexed
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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TTK protein, human
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Cisplatin