Mps1 inhibitors synergise with low doses of taxanes in promoting tumour cell death by enhancement of errors in cell division

Br J Cancer. 2018 Jun;118(12):1586-1595. doi: 10.1038/s41416-018-0081-2. Epub 2018 May 8.

Abstract

Background: Chromosomal instability (CIN) is a common trait of cancer characterised by the continuous gain and loss of chromosomes during mitosis. Excessive levels of CIN can suppress tumour growth, providing a possible therapeutic strategy. The Mps1/TTK kinase has been one of the prime targets to explore this concept, and indeed Mps1 inhibitors synergise with the spindle poison docetaxel in inhibiting the growth of tumours in mice.

Methods: To investigate how the combination of docetaxel and a Mps1 inhibitor (Cpd-5) promote tumour cell death, we treated mice transplanted with BRCA1-/-;TP53-/- mammary tumours with docetaxel and/or Cpd-5. The tumours were analysed regarding their histopathology, chromosome segregation errors, copy number variations and cell death to understand the mechanism of action of the drug combination.

Results: The enhanced efficacy of combining an Mps1 inhibitor with clinically relevant doses of docetaxel is associated with an increase in multipolar anaphases, aberrant nuclear morphologies and cell death. Tumours treated with docetaxel and Cpd-5 displayed more genomic deviations, indicating that chromosome stability is affected mostly in the combinatorial treatment.

Conclusions: Our study shows that the synergy between taxanes and Mps1 inhibitors depends on increased errors in cell division, allowing further optimisation of this treatment regimen for cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • BRCA1 Protein / deficiency
  • BRCA1 Protein / genetics
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Death / drug effects
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Docetaxel / administration & dosage
  • Docetaxel / pharmacology*
  • Drug Synergism
  • Female
  • Humans
  • MCF-7 Cells
  • Mice
  • Mitosis / drug effects
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Paclitaxel / administration & dosage
  • Paclitaxel / pharmacology*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics
  • Xenograft Model Antitumor Assays

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • Cell Cycle Proteins
  • Protein Kinase Inhibitors
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Docetaxel
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • TTK protein, human
  • Paclitaxel