Microtubule stabilizing agents (MSAs) are an important class of therapeutic compounds used for the treatment of multiple cancers. Subtle differences in the affect of MSAs can provide an opportunity to increase the susceptibility of specific protein targets critical to the cell cycle. The epothilones are a relatively new class of MSAs effective for the treatment of Taxol® resistant breast cancer and the basis for the drug, Ixempra®. Using live cell analysis, we have shown that epothilones are effective at arresting cell division specifically at prometaphase. At this same stage of cell division, aurora B kinases are involved in chromosomal separation and inhibition of these kinases causes a frozen phenotype. When combining epothilone with aurora kinase inhibitors (AKIs), we observed a highly-penetrant mitotic defect that induced cell death. This defect was distinct from those caused by treatment with either epothilone or AKIs alone. More detailed analysis of this combinatorial defect identified similarities to Progeria Syndrome in humans, with formation of highly-lobulated nuclei and asymmetric deposition of nuclear lamina proteins. We will present a new model in which the combination of epothilones with AKIs shifts the specificity of aurora B from prometaphase substrates to telophase substrates. This outcome for combinatorial drug treatment provides a novel mechanism of action with broad potential.

Combination therapy with epothilone and aurora kinase inhibitors induces a novel form of cell death

249th National Meeting (2015)

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