TY - JOUR
T1 - Effects of the selective MPS1 inhibitor MPS1-IN-3 on glioblastoma sensitivity to antimitotic drugs
AU - Tannous, Bakhos A
AU - Kerami, Mariam
AU - Van der Stoop, Petra M
AU - Kwiatkowski, Nicholas
AU - Wang, Jinhua
AU - Zhou, Wenjun
AU - Kessler, Almuth F
AU - Lewandrowski, Grant
AU - Hiddingh, Lotte
AU - Sol, Nik
AU - Lagerweij, Tonny
AU - Wedekind, Laurine
AU - Niers, Johanna M
AU - Barazas, Marco
AU - Nilsson, R Jonas A
AU - Geerts, Dirk
AU - De Witt Hamer, Philip C
AU - Hagemann, Carsten
AU - Vandertop, W Peter
AU - Van Tellingen, Olaf
AU - Noske, David P
AU - Gray, Nathanael S
AU - Würdinger, Thomas
PY - 2013/9/4
Y1 - 2013/9/4
N2 - BACKGROUND: Glioblastomas exhibit a high level of chemotherapeutic resistance, including to the antimitotic agents vincristine and taxol. During the mitotic agent-induced arrest, glioblastoma cells are able to perform damage-control and self-repair to continue proliferation. Monopolar spindle 1 (MPS1/TTK) is a checkpoint kinase and a gatekeeper of the mitotic arrest.METHODS: We used glioblastoma cells to determine the expression of MPS1 and to determine the effects of MPS1 inhibition on mitotic errors and cell viability in combination with vincristine and taxol. The effect of MPS1 inhibition was assessed in different orthotopic glioblastoma mouse models (n = 3-7 mice/group). MPS1 expression levels were examined in relation to patient survival.RESULTS: Using publicly available gene expression data, we determined that MPS1 overexpression corresponds positively with tumor grade and negatively with patient survival (two-sided t test, P < .001). Patients with high MPS1 expression (n = 203) had a median and mean survival of 487 and 913 days (95% confidence intervals [CI] = 751 to 1075), respectively, and a 2-year survival rate of 35%, whereas patients with intermediate MPS1 expression (n = 140) had a median and mean survival of 858 and 1183 days (95% CI = 1177 to 1189), respectively, and a 2-year survival rate of 56%. We demonstrate that MPS1 inhibition by RNAi results in sensitization to antimitotic agents. We developed a selective small-molecule inhibitor of MPS1, MPS1-IN-3, which caused mitotic aberrancies in glioblastoma cells and, in combination with vincristine, induced mitotic checkpoint override, increased aneuploidy, and augmented cell death. MPS1-IN-3 sensitizes glioblastoma cells to vincristine in orthotopic mouse models (two-sided log-rank test, P < .01), resulting in prolonged survival without toxicity.CONCLUSIONS: Our results collectively demonstrate that MPS1, a putative therapeutic target in glioblastoma, can be selectively inhibited by MPS1-IN-3 sensitizing glioblastoma cells to antimitotic drugs.
AB - BACKGROUND: Glioblastomas exhibit a high level of chemotherapeutic resistance, including to the antimitotic agents vincristine and taxol. During the mitotic agent-induced arrest, glioblastoma cells are able to perform damage-control and self-repair to continue proliferation. Monopolar spindle 1 (MPS1/TTK) is a checkpoint kinase and a gatekeeper of the mitotic arrest.METHODS: We used glioblastoma cells to determine the expression of MPS1 and to determine the effects of MPS1 inhibition on mitotic errors and cell viability in combination with vincristine and taxol. The effect of MPS1 inhibition was assessed in different orthotopic glioblastoma mouse models (n = 3-7 mice/group). MPS1 expression levels were examined in relation to patient survival.RESULTS: Using publicly available gene expression data, we determined that MPS1 overexpression corresponds positively with tumor grade and negatively with patient survival (two-sided t test, P < .001). Patients with high MPS1 expression (n = 203) had a median and mean survival of 487 and 913 days (95% confidence intervals [CI] = 751 to 1075), respectively, and a 2-year survival rate of 35%, whereas patients with intermediate MPS1 expression (n = 140) had a median and mean survival of 858 and 1183 days (95% CI = 1177 to 1189), respectively, and a 2-year survival rate of 56%. We demonstrate that MPS1 inhibition by RNAi results in sensitization to antimitotic agents. We developed a selective small-molecule inhibitor of MPS1, MPS1-IN-3, which caused mitotic aberrancies in glioblastoma cells and, in combination with vincristine, induced mitotic checkpoint override, increased aneuploidy, and augmented cell death. MPS1-IN-3 sensitizes glioblastoma cells to vincristine in orthotopic mouse models (two-sided log-rank test, P < .01), resulting in prolonged survival without toxicity.CONCLUSIONS: Our results collectively demonstrate that MPS1, a putative therapeutic target in glioblastoma, can be selectively inhibited by MPS1-IN-3 sensitizing glioblastoma cells to antimitotic drugs.
KW - 2-Aminopurine/analogs & derivatives
KW - Animals
KW - Antimitotic Agents/pharmacology
KW - Antineoplastic Agents, Phytogenic/administration & dosage
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Cell Cycle Proteins/antagonists & inhibitors
KW - Cell Survival/drug effects
KW - Drug Resistance, Neoplasm
KW - France
KW - Frozen Sections
KW - Gene Expression Regulation, Neoplastic
KW - Glioblastoma/drug therapy
KW - Humans
KW - M Phase Cell Cycle Checkpoints/drug effects
KW - Mice
KW - Mice, Nude
KW - Netherlands
KW - Paclitaxel/administration & dosage
KW - Protein Serine-Threonine Kinases/antagonists & inhibitors
KW - Protein-Tyrosine Kinases/antagonists & inhibitors
KW - RNA Interference/drug effects
KW - United States
KW - Up-Regulation
KW - Vincristine/administration & dosage
KW - Xenograft Model Antitumor Assays
KW - ortho-Aminobenzoates/pharmacology
U2 - 10.1093/jnci/djt168
DO - 10.1093/jnci/djt168
M3 - Article
C2 - 23940287
SN - 0027-8874
VL - 105
SP - 1322
EP - 1331
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 17
ER -