Abstract
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.
Highlights
Breast cancer is the most prevalent cancer worldwide, with 2002 global statistics reporting >1 million new cases diagnosed annually and >400,000 deaths (Parkin et al, 2005)
Molecular characterization of breast cancer has led to the determination of a number of different subtypes and gene expression signatures that correlate with clinical factors such as prognosis, tumor recurrence, and survival (Sørlie et al, 2001; Wang et al, 2005)
As seen in other tumor cell lines, the anti-proliferative activity patient-derived breast cancer tissue has indicated that estrogen of sagopilone is more potent than that of paclitaxel or ixabepi- receptor α (ERα) positive tumors were more resistant to six antilone across breast cancer cell lines
Summary
Breast cancer is the most prevalent cancer worldwide, with 2002 global statistics reporting >1 million new cases diagnosed annually and >400,000 deaths (Parkin et al, 2005). There has been a shift toward more tailored therapies against specific disease types in the clinic (Hatake et al, 2007), for example, the addition of trastuzumab/lapatinib to chemotherapy for HER2-positive tumors This combination approach is changing the standards of care in breast cancer (National Comprehensive Cancer Network, 2008). Optimal treatment for patients suffering from this heterogeneous disease will increasingly rely on gene expression/biomarker analysis to determine the most appropriate patient population for each treatment and the best therapy combinations for each patient, balancing response, and tolerability while avoiding resistance This remains a major challenge (Gonzalez-Angulo et al, 2007) and it is important to combine the development of new therapeutic agents for patients with breast cancer with research into optimal patient populations and tailored treatment combinations at the earliest opportunity
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