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

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.

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Abbreviations

Cis/Pem:

cisplatin/pemetrexed

MM:

malignant mesothelioma

Mps-1:

monopolar spindle 1

TTK:

dual specificity Thr/Tyr kinase.

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Acknowledgements

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.

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Correspondence to M Carbone or H Yang.

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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.

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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

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