Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic mps1 kinase inhibitor NMS-P715

Roger B. Slee, Brenda Grimes, Ruchi Bansal, Jesse Gore, Corinne Blackburn, Lyndsey Brown, Rachel Gasaway, Jaesik Jeong, Jose Victorino, Keith L. March, Riccardo Colombo, Brittney-Shea Herbert, Murray Korc

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Abstract

Most solid tumors, including pancreatic ductal adenocarcinoma (PDAC), exhibit structural and numerical chromosome instability (CIN). Although often implicated as a driver of tumor progression and drug resistance, CIN also reduces cell fitness and poses a vulnerability that can be exploited therapeutically. The spindle assembly checkpoint (SAC) ensures correct chromosome-microtubule attachment, thereby minimizing chromosome segregation errors. Many tumors exhibit upregulation of SAC components such as MPS1, which may help contain CIN within survivable limits. Prior studies showed that MPS1 inhibition with the small molecule NMS-P715 limits tumor growth in xenograft models. In cancer cell lines, NMSP715 causes cell death associated with impaired SAC function and increased chromosome missegregation. Although normal cells appeared more resistant, effects on stem cells, which are the dose-limiting toxicity of most chemotherapeutics, were not examined. Elevated expression of 70 genes (CIN70), including MPS1, provides a surrogate measure of CIN and predicts poor patient survival in multiple tumor types. Our new findings show that the degree of CIN70 upregulation varies considerably among PDAC tumors, with higher CIN70 gene expression predictive of poor outcome.We identified a 25 gene subset (PDAC CIN25) whose overexpression was most strongly correlated with poor survival and included MPS1. In vitro, growth of human and murine PDAC cells is inhibited by NMS-P715 treatment, whereas adipose-derived human mesenchymal stem cells are relatively resistant and maintain chromosome stability upon exposure to NMS-P715. These studies suggest that NMS-P715 could have a favorable therapeutic index and warrant further investigation of MPS1 inhibition as a new PDAC treatment strategy. Mol Cancer Ther; 13(2); 307-15.

Original languageEnglish
Pages (from-to)307-315
Number of pages9
JournalMolecular Cancer Therapeutics
Volume13
Issue number2
DOIs
StatePublished - Feb 2014

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Adenocarcinoma
Phosphotransferases
Chromosomal Instability
Growth
M Phase Cell Cycle Checkpoints
Neoplasms
Up-Regulation
Chromosomes
Gene Expression
Chromosome Segregation
Survival
N-(2,6-diethylphenyl)-1-methyl-8-((4-((1-methylpiperidin-4-yl)carbamoyl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo(4,3-h)quinazoline-3-carboxamide
Mesenchymal Stromal Cells
Drug Resistance
Heterografts
Microtubules
Cause of Death
Cell Death
Stem Cells
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic mps1 kinase inhibitor NMS-P715. / Slee, Roger B.; Grimes, Brenda; Bansal, Ruchi; Gore, Jesse; Blackburn, Corinne; Brown, Lyndsey; Gasaway, Rachel; Jeong, Jaesik; Victorino, Jose; March, Keith L.; Colombo, Riccardo; Herbert, Brittney-Shea; Korc, Murray.

In: Molecular Cancer Therapeutics, Vol. 13, No. 2, 02.2014, p. 307-315.

Research output: Contribution to journalArticle

Slee, RB, Grimes, B, Bansal, R, Gore, J, Blackburn, C, Brown, L, Gasaway, R, Jeong, J, Victorino, J, March, KL, Colombo, R, Herbert, B-S & Korc, M 2014, 'Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic mps1 kinase inhibitor NMS-P715', Molecular Cancer Therapeutics, vol. 13, no. 2, pp. 307-315. https://doi.org/10.1158/1535-7163.MCT-13-0324
Slee, Roger B. ; Grimes, Brenda ; Bansal, Ruchi ; Gore, Jesse ; Blackburn, Corinne ; Brown, Lyndsey ; Gasaway, Rachel ; Jeong, Jaesik ; Victorino, Jose ; March, Keith L. ; Colombo, Riccardo ; Herbert, Brittney-Shea ; Korc, Murray. / Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic mps1 kinase inhibitor NMS-P715. In: Molecular Cancer Therapeutics. 2014 ; Vol. 13, No. 2. pp. 307-315.
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