Effects of the selective MPS1 inhibitor MPS1-IN-3 on glioblastoma sensitivity to antimitotic drugs.
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.
Neuroscience Center and Molecular Neurogenetics Unit, Departments of Neurology, Harvard Medical School, Boston, MA, USA.
Bakhos A
BA
Tannous
Mariam
M
Kerami
Petra M
PM
Van der Stoop
Nicholas
N
Kwiatkowski
Jinhua
J
Wang
Wenjun
W
Zhou
Almuth F
AF
Kessler
Grant
G
Lewandrowski
Lotte
L
Hiddingh
Nik
N
Sol
Tonny
T
Lagerweij
Laurine
L
Wedekind
Johanna M
JM
Niers
Marco
M
Barazas
R Jonas A
RJ
Nilsson
Dirk
D
Geerts
Philip C
PC
De Witt Hamer
Carsten
C
Hagemann
W Peter
WP
Vandertop
Olaf
O
Van Tellingen
David P
DP
Noske
Nathanael S
NS
Gray
Thomas
T
Würdinger
D015075:2-Aminopurine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D050256:Antimitotic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005602:France; D005629:Frozen Sections; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009426:Netherlands; D017239:Paclitaxel / Q000008:administration & dosage; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D034622:RNA Interference / Q000187:drug effects; D014481:United States; D015854:Up-Regulation; D014750:Vincristine / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
C584096:1-(4-(6-(2-(isopropylsulfonyl)phenylamino)-9H-purin-2-ylamino)-3-ethoxyphenyl)piperidin-4-ol; D050256:Antimitotic Agents; D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D062367:ortho-Aminobenzoates; D015075:2-Aminopurine; D014750:Vincristine; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human; D017239:Paclitaxel