RT-18 * TARGETING MPS1 ENHANCES RADIOSENSITIZATION OF HUMAN GLIOBLASTOMA BY MODULATING DNA REPAIR PROTEINS

Abstract

During the cell cycle, genomic stability requires accurate chromosome segregation. Errors in this process can cause aneuploidy, leading to tumorigenesis. To ensure faithful chromosome segregation, cells use the spindle assembly checkpoint (SAC) mechanism. However, in aneuploid cancer cells components of the SAC machinery are frequently altered. Thus, targeting the components of SAC machinery required for the growth of aneuploid cells may thus offer a cancer cell specific therapeutic approach. Monopolar spindle 1 (MPS1) is an essential SAC kinase involved in determining spindle integrity. MPS1 is overexpressed in a wide range of tumors and is required for tumor cell proliferation; there is thus increased interest in targeting MPS1 for cancer treatment. In this study, we have analyzed the mechanistic basis of the effects of inhibiting MPS1 in glioblastoma multiforme (GBM). We show that the inhibition of MPS1 in conjunction with radiation reduces GBM cell growth, and clonogenic survival and that this is associated with mitotic cell arrest and induction of mitotic catastrophe. MNS-P715 not alone, but along with fractionated doses of radiation significantly enhanced the tumor growth delay. Using gene expression profiling of GBM cells in which MPS1 was silenced we identified altered expression of genes associated with DNA damage, DNA repair, and DNA replication, including PRKDC, the DNA-dependent protein kinase (DNAPK). Inhibition of MPS1 blocked two important DNA repair pathways, non-homologous end joining and homologous recombination. To our knowledge, this is the first report demonstrating a role for MPS1 in DNA repair. Data mining of publically available databases showed the clinical relevance of MPS1 as an important cancer target in GBM. We conclude that inhibiting MPS1 kinase in combination with DNA damage, including irradiation, could represent a promising new approach to cancer therapy.