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.
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monopolar spindle 1
dual specificity Thr/Tyr kinase.
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This work was supported in part by the NCI-R01 CA198138 to MC; by the NCI-R01 CA160715 to HY; and by the University of Hawai’i Foundation, which received an unrestricted gift to support MM research from Honeywell International Inc., to MC; and from United-4-a-Cure, to MC and HY CFI-402257 was synthesized and provided by our collaborators and co-authors at the Campbell Family Institute for Breast Cancer Research, Toronto, Canada.
MC provides consultation for mesothelioma diagnosis. All other authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in, or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Supplementary Information accompanies this paper on the Oncogene website
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Szymiczek, A., Carbone, M., Pastorino, S. et al. Inhibition of the spindle assembly checkpoint kinase Mps-1 as a novel therapeutic strategy in malignant mesothelioma. Oncogene 36, 6501–6507 (2017). https://doi.org/10.1038/onc.2017.266
Journal of Cancer Research and Clinical Oncology (2019)