Abstract 1584: Targeting the mitotic checkpoint with inhibition of MPS1 kinase enhances radiosensitivity of glioblastoma cancer cells.

Abstract

Abstract During the cell cycle, genomic stability requires accurate chromosome segregation. Errors in this process can cause aneuploidy and lead to tumorigenesis. To ensure faithful chromosome segregation, cells develop a mechanism called the spindle assembly checkpoint (SAC). Cancer cells are addicted to the components of SAC machinery for a faithful entry of the cell into anaphase. Thus, targeting the molecular mechanisms required for the growth of aneuploid cells may be a more cancer cell specific therapeutic approach applicable to broader tumor histologies. Previously, using a siRNA based RNAi screen we identified MPS1 kinase, (also known as TTK) as an important kinase for GBM cell survival. MPS1 is an essential SAC enzyme aberrantly overexpressed in a wide range of tumors and necessary for tumor cell proliferation. We observed inhibition of GBM cell growth when MPS1 was downregulated by number of MPS1 specific siRNAs. This was further validated using a selective and orally bioavailable MPS1 inhibitor NMS-P715 in various in-vitro cell assays. The inhibition of cell death was induced partly by apoptosis; however, the major mechanism was mitotic catastrophe. Cells treated with NMS-P715 showed an increase in cells in G2-M phase of cell cycle compared to control cells followed by mitotic catastrophe. Moreover, inhibition of MPS1 resulted in radiosensitization of GBM cells. We observed decrease in DNA damage repair and significant retention of γH2AX foci after combination of radiation (RT) with NMS-P715 compared to individual treatments. Next, radiation in combination with NMS-P715 inhibited cell survival ability of GBM cells in a colony formation assay. Further, NMS-P715 could inhibit GBM tumor growth in an orthotopic brain tumor model. Finally, in order to determine MPS1 associated molecular pathways, we compared gene expression profile in MPS1 knockdown cells compared to the control by microarray analysis. Ingenuity pathway and Gene Set Enrichment Analysis were used to investigate the biological relevance of the MPS1 modulated genes. We identified genes important in cell assembly, cell organization, DNA repair and cell death pathways. Thus, inhibiting MPS1 kinase in combination with radiation could represent a promising new approach to GBM therapy. Citation Format: Anita T. Tandle, Ryan Hanson, Uday B. Maachani, Tamalee Meushaw, Shuping Zhao, Uma Shankavaram, Philip Tofilon, Natasha J. Caplen, Kevin Camphausen. Targeting the mitotic checkpoint with inhibition of MPS1 kinase enhances radiosensitivity of glioblastoma cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1584. doi:10.1158/1538-7445.AM2013-1584