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Mitotic checkpoint kinase Mps1 has a role in normal physiology which impacts clinical utility

Academic Article
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Overview

authors

  • Martinez, R.
  • Blasina, A.
  • Hallin, J. F.
  • Hu, W.
  • Rymer, I.
  • Fan, J.
  • Hoffman, R. L.
  • Murphy, S.
  • Marx, M.
  • Yanochko, G.
  • Trajkovic, D.
  • Dinh, D.
  • Timofeevski, S.
  • Zhu, Z.
  • Sun, Peiqing
  • Lappin, P. B.
  • Murray, B. W.

publication date

  • 2015

journal

  • PLoS One  Journal

abstract

  • Cell cycle checkpoint intervention is an effective therapeutic strategy for cancer when applied to patients predisposed to respond and the treatment is well-tolerated. A critical cell cycle process that could be targeted is the mitotic checkpoint (spindle assembly checkpoint) which governs the metaphase-to-anaphase transition and insures proper chromosomal segregation. The mitotic checkpoint kinase Mps1 was selected to explore whether enhancement in genomic instability is a viable therapeutic strategy. The basal-a subset of triple-negative breast cancer was chosen as a model system because it has a higher incidence of chromosomal instability and Mps1 expression is up-regulated. Depletion of Mps1 reduces tumor cell viability relative to normal cells. Highly selective, extremely potent Mps1 kinase inhibitors were created to investigate the roles of Mps1 catalytic activity in tumor cells and normal physiology (PF-7006, PF-3837; Ki<0.5 nM; cellular IC50 2-6 nM). Treatment of tumor cells in vitro with PF-7006 modulates expected Mps1-dependent biology as demonstrated by molecular and phenotypic measures (reduced pHH3-Ser10 levels, shorter duration of mitosis, micro-nucleation, and apoptosis). Tumor-bearing mice treated with PF-7006 exhibit tumor growth inhibition concomitant with pharmacodynamic modulation of a downstream biomarker (pHH3-Ser10). Unfortunately, efficacy only occurs at drug exposures that cause dose-limiting body weight loss, gastrointestinal toxicities, and neutropenia. Mps1 inhibitor toxicities may be mitigated by inducing G1 cell cycle arrest in Rb1-competent cells with the cyclin-dependent kinase-4/6 inhibitor palbociclib. Using an isogenic cellular model system, PF-7006 is shown to be selectively cytotoxic to Rb1-deficient cells relative to Rb1-competent cells (also a measure of kinase selectivity). Human bone marrow cells pretreated with palbociclib have decreased PF-7006-dependent apoptosis relative to cells without palbociclib pretreatment. Collectively, this study raises a concern that single agent therapies inhibiting Mps1 will not be well-tolerated clinically but may be when combined with a selective CDK4/6 drug.

subject areas

  • Animals
  • Apoptosis
  • Bone Marrow Cells
  • Breast Neoplasms
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Female
  • G1 Phase Cell Cycle Checkpoints
  • Histones
  • Humans
  • Intestine, Small
  • Mice
  • Mice, SCID
  • Mitosis
  • Phosphorylation
  • Piperazines
  • Protein Kinase Inhibitors
  • Protein-Serine-Threonine Kinases
  • Protein-Tyrosine Kinases
  • Pyridines
  • RNA Interference
  • RNA, Small Interfering
  • Rats
  • Transplantation, Heterologous
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Identity

PubMed Central ID

  • PMC4580473

International Standard Serial Number (ISSN)

  • 1932-6203

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0138616

PubMed ID

  • 26398286
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Additional Document Info

start page

  • e0138616

volume

  • 10

issue

  • 9

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