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

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

Author information

1
Division of Cell Biology and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands.
2
Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands.
3
Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands.
4
Division of Molecular Pathology and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands.
5
Transgenic Core Facility, Mouse Clinic for Cancer and Aging (MCCA), The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands.
6
Genomics Core Facility, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands.
7
Laboratory of Clinical Chemistry and Hematology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands.
8
Division of Cell Biology and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands. r.medema@nki.nl.

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.

PMID:
29736010
PMCID:
PMC6008333
[Available on 2019-06-12]
DOI:
10.1038/s41416-018-0081-2

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