Sagopilone, a fully synthetic
epothilone, is a microtubule-
stabilizing agent optimized for high in vitro and in vivo activity against a broad range of
tumor models, including those resistant to
paclitaxel and other systemic treatments.
Sagopilone development is accompanied by translational research studies to evaluate the molecular mode of action, to recognize mechanisms leading to resistance, to identify predictive response
biomarkers, and to establish a rationale for combination with different
therapies. Here, we profiled
sagopilone activity in
breast cancer cell lines. To analyze the mechanisms of mitotic arrest and apoptosis and to identify additional targets and
biomarkers, an
siRNA-based RNAi
drug modifier screen interrogating 300 genes was performed in four
cancer cell lines. Defects of the spindle assembly checkpoint (SAC) were identified to cause resistance against
sagopilone-induced mitotic arrest and apoptosis. Potential
biomarkers for resistance could therefore be functional defects like polymorphisms or mutations in the SAC, particularly in the central SAC
kinase BUB1B. Moreover, chromosomal heterogeneity and
polyploidy are also potential
biomarkers of
sagopilone resistance since they imply an increased tolerance for aberrant mitosis. RNAi screening further demonstrated that the
sagopilone-induced mitotic arrest can be enhanced by concomitant inhibition of mitotic
kinesins, thus suggesting a potential combination
therapy of
sagopilone with a KIF2C (MCAK)
kinesin inhibitor. However, the combination of
sagopilone and inhibition of the prophase
kinesin KIF11 (EG5) is antagonistic, indicating that the
kinesin inhibitor has to be highly specific to bring about the required therapeutic benefit.