6INTHE INTERFACE BETWEEN CANCER NUMERICAL AND STRUCTURAL CHROMOSOMAL INSTABILITY: MECHANISMS ACCELERATING CANCER DIVERSITY.

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.