6IN - The interface between cancer numerical and structural chromosomal instability: Mechanisms accelerating cancer diversity

Date 29 September 2014
Event ESMO 2014
Session Genomic instability from bench to bedside
Topics Cancer Biology
Basic Scientific Principles
Presenter René Medema
Citation Annals of Oncology (2014) 25 (suppl_4): iv4-iv4. 10.1093/annonc/mdu290
Authors R. Medema1, A.R.R. Maia1, A. Janssen1, A. Koch1, U. Boon2, R.C. Buijsman3, G.J.R. Zaman3, J. Jonkers2
  • 1Cell Biology, Netherlands Cancer Institute, 1066 CX - Amsterdam/NL
  • 2Molecular Pathology, Netherlands Cancer Institute, 1066 CX - Amsterdam/NL
  • 3Medicinal Chemistry, Netherlands Translational Research Center, 5342CC - Oss/NL

Abstract

Body

Abstract:

Various types of chromosomal aberrations, including numerical (aneuploidy) and structural (e.g. translocations, deletions), are commonly found in human tumors. Aneuploidy is a direct consequence of chromosome segregation errors in mitosis, but recent reports have shown that chromosome segregation errors can also result in structural chromosome aberrations. We found that chromosomes that missegregate are frequently damaged during cytokinesis. Importantly, we found that these double strand breaks can lead to unbalanced translocations in the daughter cells. These and other data shed light on the mechanisms that can facilitate rapid cancer diversification. To prevent chromosome segreation errors, cells depend on the Spindle Assembly Checkpoint (SAC), a complex signaling network that allows time for proper chromosome bi-orientation. We are testing a specific small molecule kinase inhibitor of Mps1, an important SAC component that sustains SAC function, but also contributes to chromosome alignment. In cultured mammalian cells Mps1 inhibition accelerates mitosis, and prevents full chromosome alignment, resulting in chromosome segregation errors. Proliferation assays indicate that tumor cell lines are more sensitive to Mps1 inhibition than normal non-transformed cell lines. This observation lead us to explore Mps1 inhibition as a tool to specifically target cancer cells, without compromising normal stable cells. We used FVB mouse models to characterize the effects of Mps1 inhibition in vivo. Cell lines derived from BRCA1- and p53-deficient breast tumors display impaired cell proliferation upon Mps1 inhibition and we observe a synergistic increase when combined with docetaxel treatment. In a model for hereditary triple-negative breast cancer (BRCA1f/f; p53f/f model), treatment of a combination of Mps1 inhibitor and docetaxel resulted in tumor regression and an increase in mouse survival. A higher percentage of anaphase figures with lagging chromosomes was observed in tumors and in the gut. These data support Mps1 inhibition in combination with anti-mitotic agents as a novel therapeutic approach for triple negative breast cancer.

Disclosure:

R.C. Buijsman: Rogier C. Buijsman is founder and shareholder of NTRC

G.J.R. Zaman: Guido J.R. Zaman is founder and shareholder of NTRC

All other authors have declared no conflicts of interest.