MPS1 kinase as a potential therapeutic target in medulloblastoma

Alimova,Irina; Ng,June; Harris,Peter; Birks,Diane; Donson,Andrew; Taylor,Michael D.; Foreman,Nicholas K.; Venkataraman,Sujatha; Vibhakar,Rajeev

doi:10.3892/or.2016.5085

MPS1 kinase as a potential therapeutic target in medulloblastoma

Authors:
- Irina Alimova
- June Ng
- Peter Harris
- Diane Birks
- Andrew Donson
- Michael D. Taylor
- Nicholas K. Foreman
- Sujatha Venkataraman
- Rajeev Vibhakar
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Affiliations: Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA, Department of Neurosurgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA, Division of Neurosurgery, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
Published online on: September 12, 2016 https://doi.org/10.3892/or.2016.5085
Pages: 2633-2640

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Abstract

Medulloblastoma is the most common type of malignant brain tumor that affects children. Although recent advances in chemotherapy and radiation have improved outcomes, high-risk patients perform poorly with significant morbidity. Gene expression profiling has revealed that monopolar spindle 1 (MPS1) (TTK1) is highly expressed in medulloblastoma patient samples compared to that noted in normal cerebellum. MPS1 is a key regulator of the spindle assembly checkpoint (SAC), a mitotic mechanism specifically required for proper chromosomal alignment and segregation. The SAC can be activated in aneuploid cancer cells and MPS1 is overexpressed in many types of cancers. A previous study has demonstrated the effectiveness of inhibiting MPS1 with small-molecule inhibitors, but the role of MPS1 in medulloblastoma is unknown. In the present study, we demonstrated that MPS1 inhibition by shRNA or with a small-molecule drug, NMS-P715, resulted in decreased cell growth, inhibition of clonogenic potential and induction of apoptosis in cells belonging to both the Shh and group 3 medulloblastoma genomic signature. These findings highlight MPS1 as a rational therapeutic target for medulloblastoma.

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