title: Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic MPS1 kinase inhibitor NMS-P715.
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, NMS-P715 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.
authors.affiliation: Indiana University School of Medicine (IUSM) Department of Medical and Molecular Genetics,Indiana. Nerviano Medical Sciences, Nerviano, Italy.|IU Melvin and Bren Simon Cancer Center (IUSCC), Nerviano Medical Sciences, Nerviano, Italy.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Slee
authors.affiliation: Indiana University School of Medicine (IUSM) Department of Medical and Molecular Genetics,Indiana. Nerviano Medical Sciences, Nerviano, Italy.|IU Melvin and Bren Simon Cancer Center (IUSCC), Nerviano Medical Sciences, Nerviano, Italy.|IUSCC Center for Pancreatic Cancer Research, Nerviano Medical Sciences, Nerviano, Italy.
authors.forename: Brenda R
authors.initials: BR
authors.lastname: Grimes
authors.affiliation: Indiana University School of Medicine (IUSM) Department of Medical and Molecular Genetics,Indiana. Nerviano Medical Sciences, Nerviano, Italy.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Bansal
authors.affiliation: IUSM Department of Medicine, Nerviano Medical Sciences, Nerviano, Italy.
authors.forename: Jesse
authors.initials: J
authors.lastname: Gore
authors.affiliation: Indiana University School of Medicine (IUSM) Department of Medical and Molecular Genetics,Indiana. Nerviano Medical Sciences, Nerviano, Italy.
authors.forename: Corinne
authors.initials: C
authors.lastname: Blackburn
authors.affiliation: Indiana University School of Medicine (IUSM) Department of Medical and Molecular Genetics,Indiana. Nerviano Medical Sciences, Nerviano, Italy.
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Brown
authors.affiliation: Indiana University School of Medicine (IUSM) Department of Medical and Molecular Genetics,Indiana. Nerviano Medical Sciences, Nerviano, Italy.
authors.forename: Rachel
authors.initials: R
authors.lastname: Gasaway
authors.affiliation: IUSM Department of Biostatistics, Nerviano Medical Sciences, Nerviano, Italy.
authors.forename: Jaesik
authors.initials: J
authors.lastname: Jeong
authors.affiliation: Indiana University School of Medicine (IUSM) Department of Medical and Molecular Genetics,Indiana. Nerviano Medical Sciences, Nerviano, Italy.|California State University Dominguez Hills, Nerviano Medical Sciences, Nerviano, Italy.
authors.forename: Jose
authors.initials: J
authors.lastname: Victorino
authors.affiliation: IUSM Department of Medicine, Nerviano Medical Sciences, Nerviano, Italy.|IUSM Department of Biochemistry and Molecular Biology, Nerviano Medical Sciences, Nerviano, Italy.|Krannert Institute of Cardiology, Nerviano Medical Sciences, Nerviano, Italy.|Indiana Center for Vascular Biology, Nerviano Medical Sciences, Nerviano, Italy.|R.L. Roudebush Veterans Affairs Medical Center, Nerviano Medical Sciences, Nerviano, Italy.
authors.forename: Keith L
authors.initials: KL
authors.lastname: March
authors.affiliation: Indianapolis, Indiana. Nerviano Medical Sciences, Nerviano, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Colombo
authors.affiliation: Indiana University School of Medicine (IUSM) Department of Medical and Molecular Genetics,Indiana. Nerviano Medical Sciences, Nerviano, Italy.|IU Melvin and Bren Simon Cancer Center (IUSCC), Nerviano Medical Sciences, Nerviano, Italy.
authors.forename: Brittney-Shea
authors.initials: BS
authors.lastname: Herbert
authors.affiliation: IU Melvin and Bren Simon Cancer Center (IUSCC), Nerviano Medical Sciences, Nerviano, Italy.|IUSCC Center for Pancreatic Cancer Research, Nerviano Medical Sciences, Nerviano, Italy.|IUSM Department of Medicine, Nerviano Medical Sciences, Nerviano, Italy.|IUSM Department of Biochemistry and Molecular Biology, Nerviano Medical Sciences, Nerviano, Italy.
authors.forename: Murray
authors.initials: M
authors.lastname: Korc
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D016019:Survival Analysis; D013997:Time Factors; D059467:Transcriptome
chemical_list: D018797:Cell Cycle Proteins; C555141: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; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011799:Quinazolines; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human