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

Our plain-English summary of Inhibition of the spindle assembly checkpoint kinase Mps-1 as a novel therapeutic strategy in malignant mesothelioma, by A. Szymiczek, M. Carbone, S. Pastorino, et al (Oncogene, 2017).

The study

• Authors: A. Szymiczek, M. Carbone, S. Pastorino, A. Napolitano, M. Tanji, M. Minaai, I. Pagano, J.M. Mason, H.I. Pass, M.R. Bray, T.W. Mak, H. Yang
• Journal: Oncogene
• Published: 2017;36(46):6501-6507
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory and animal study tested whether blocking Mps-1, a protein that guards chromosome sorting during cell division, could slow malignant mesothelioma. Asbestos exposure was not studied. In public data on 56 mesothelioma patients, higher Mps-1 levels went with shorter survival: median survival was 254 days in the high-Mps-1 group versus 699 days in the low group. Mps-1 levels were higher in mesothelioma cell lines than in normal mesothelial cells. In lab dishes, the experimental drug CFI-402257 caused cell-division errors and death of mesothelioma cells. It left three normal mesothelial cultures largely unaffected at the same concentrations, and it acted synergistically with cisplatin. In mice with implanted mouse mesothelioma cells, the drug alone reduced tumor growth compared with an inactive vehicle, though less than cisplatin plus pemetrexed. Given after that chemotherapy, it significantly delayed tumor growth, and treated mice lived longer. The authors concluded that the drug fits the criteria for further clinical investigation, and they suggested using it alongside standard chemotherapy. Funding included an unrestricted gift from Honeywell International Inc.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical laboratory study: analysis of a public patient database (TCGA), experiments on human mesothelioma cell lines and normal mesothelial cell cultures, and mouse experiments
• Who was studied: Survival data on 56 malignant mesothelioma patients from the public TCGA database; human MM cell lines (including Ren, Mill, Phi and Hmeso) and primary human mesothelial cultures from patients with nonmalignant conditions; 40 BALB/c mice (10 per group) injected with AB12 mouse mesothelioma cells, plus 6 mice in a short-term experiment
• Exposure: No asbestos exposure was studied. The treatment tested was the Mps-1 inhibitor CFI-402257, given to mice by mouth at 7 mg/kg daily (35 mg/kg in the short-term experiment), alone or after cisplatin plus pemetrexed. Cells were treated in the laboratory at nanomolar concentrations.
• Main results:
  • In 56 TCGA patients, Mps-1 mRNA levels correlated with shorter survival (r = -0.41; 95% CI -0.61 to -0.17; P less than 0.01)
  • Patients with high Mps-1 had shorter survival than patients with low Mps-1 (median survival 254 days vs. 699 days; HR 0.42; 95% CI 0.24 to 0.75; P less than 0.001)
  • Mps-1 mRNA expression was higher in non-epithelioid subtypes (biphasic, sarcomatoid and diffuse) than in the epithelioid subtype
  • Mps-1 expression was higher in all MM cell lines than in human mesothelial cultures (1.03 plus or minus 0.25 vs 0.13 plus or minus 0.06, P = 0.043)
  • CFI-402257 reduced MM cell viability with EC50 values of 20 to 40 nM, while three normal mesothelial cultures were largely unaffected at these concentrations
  • CFI-402257 and cisplatin had a synergistic effect in two MM cell lines (CDI = 0.652 for Hmeso; CDI = 0.86 for Mill)
  • In mice, CFI-402257 alone reduced tumor growth compared with vehicle (P = 0.0008), but less than standard chemotherapy. Added after chemotherapy, it delayed tumor growth (P less than 0.0001).
  • Overall survival of mice was prolonged in both the CFI-402257-alone group (P less than 0.0001) and the chemotherapy-then-CFI-402257 group (P = 0.004)
  • No overt toxicity or weight loss was seen in mice given CFI-402257 alone; the combination group lost less than 10% of body mass
• The authors' conclusion: The authors concluded that Mps-1 is a promising therapeutic target and that CFI-402257 fits the criteria for further clinical investigation in MM, with likely benefit in combination with established chemotherapy
• Limitations the authors state:
  • The authors noted that the higher Mps-1 expression in non-epithelioid mesotheliomas, which are more aggressive, could at least partly explain the link between high Mps-1 and poor survival

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Cisplatin, Pemetrexed (Alimta).

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