Inhibition of mitotic kinase Mps1 promotes cell death in neuroblastoma

Abstract

Neuroblastoma is the most common paediatric cancer type. Patients diagnosed with high-risk neuroblastoma have poor prognosis and occasionally tumours relapse. As a result, novel treatment strategies are needed for relapse and refractory neuroblastoma patients. Here, we found that high expression of Mps1 kinase (mitotic kinase Monopolar Spindle 1) was associated with relapsefree neuroblastoma patient outcomes and poor overall survival. Silencing and inhibition of Mps1 in neuroblastoma or PDX-derived cells promoted cell apoptosis via the caspase-dependent mitochondrial apoptotic pathway. The mechanism of cell death upon Mps1 inhibition was dependent on the polyploidization/aneuploidization of the cells before undergoing mitotic catastrophe. Furthermore, tumour growth retardation was confirmed in a xenograft mouse model after Mps1inhibitor treatment. Altogether, these results suggest that Mps1 expression and inhibition can be considered as a novel prognostic marker as well as a therapeutic strategy for the treatment of highrisk neuroblastoma patients. Neuroblastoma is the most common extra-cranial solid tumour of childhood 1,2 causing approximately 10% of all childhood cancer-related deaths 3,4. Neuroblastoma is a very heterogeneous tumour compared to other cancers. It can regress spontaneously, however, in certain cases, can undergo treatment resistance 5,6. The International Neuroblastoma Risk Group (INRG) classifies neuroblastoma tumours into very low-risk, low-risk, intermediaterisk, and high-risk 7,8. Identification of the high-risk group is important for the development of personalised medicine for neuroblastoma patients with poor prognosis. Good prognosis has been observed in children with low-or intermediate-risk after chemotherapy in combination with surgical intervention. High-risk neuroblastoma represent 40% of all diagnosed cases, and these patients have poor prognosis harbouring tumour relapse and chemoresistance, and only 50% will attain long-term survival 9,10. MYCN gene amplification has been observed in less than half of the high-risk tumours 11. In non-MYCN high-risk neuroblastoma, point mutations in TP53 and Anaplastic Lymphoma Kinase (ALK) gene mutation have been observed 12 in less than 10% of neuroblastomas 13. Recently, targeting cell cycle and in particular mitosis has been proposed as an alternative therapeutic strategy for cancer treatment 14. Spindle Assembly Checkpoint or SAC generally monitor proper mitosis by controlling the correct attachment of the chromosomes to the microtubule spindle apparatus via their kinetochores 15. Once the chromosomes are fully arranged on the metaphase plate, the SAC is turned off, and chromosome segregation as well as cell division can be engaged 16. The Mps1 kinase (Monopolar spindle1) is an important regulator of the SAC and it phosphorylates target proteins principally on tyrosines, serines, and threonines 17. The most important function of Mps1 is to ensure proper biorientation of sister chromatids on the mitotic spindle at kinetochores. In early mitosi...

The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor–resistant ER + breast cancer with mitotic aberrations

“…Once this is achieved, the checkpoint is satisfied, TTK becomes inactive, and cells progress to anaphase. Consequently, pharmacologic inactivation of the SAC by TTKi such as CFI-402257 induces premature chromosome segregation, leading to aneuploidy, genomic instability, and cell death (33,(47)(48)(49)(50)(51).…”

Cell cycle control in cancer

“…Recent work has revealed how anueploid cells can be uniquely vulnerable to SAC inhibition: although initally less sensitive than diploid cells to Mps1 inhibition, after 10 days of treatment the cumulative effect of multiple chromosomal abberations resulted in increased death and decreased proliferation specifically in aneuploid cells 196 . Several Mps1 inhibitors have been developed and show promise particularly in treating pediatric neurological malignancies 100,[197][198][199] . Inhibitors of Mps1 or other SAC components (such as Cdc20 99 ) are good candidates for a new generation of anti-mitotic targeted therapies.…”

Development of the First Covalent Monopolar Spindle Kinase 1 (MPS1/TTK) Inhibitor

“…MPS1 overexpression has been linked to poor prognosis in a variety of solid tumors, including glioblastoma, triple-negative breast and pancreatic cancer. Indeed, elevated MPS1 protein levels have been suggested as a prognostic marker for neuroblastoma [4][5][6][7][8] .…”

“…Inhibition of MPS1 by small molecules is a promising approach in cancer therapy, with the mechanism of action of SAC inactivation being complementary to that of Taxol and vinca alkaloids, i.e. overriding the SAC to cause accumulation of chromosome segregation errors which lead to cancer cell death by apoptosis [8][9][10][11] . Several reversible MPS1 inhibitors, including BAY 1161909 (Empesertib, 1) 11 , BAY 1217389 (2) 11 , BOS172722 (3) 12 and CFI-402257 (4) 13 (Figure 1A) are currently undergoing clinical trials.…”