Antimitotic agents, e.g. paclitaxel, are used extensively to treat breast and ovarian cancer. Also, at ASCO 2015, the STAMPEDE clinical trial showed that docetaxel significantly extends survival in men with prostate cancer.
Despite the proven efficacy of these drugs, there are a number of issues. Not every cancer responds and we cannot predict which cancers will/not respond. Resistance is a problem, but the mechanisms are obscure. Also, neurotoxicity due to disrupting microtubule function in non-dividing cells can be problematic.
To address these issues, ~€10bn has been spent developing 2nd generation antimitotics, resulting in excellent drugs targeting mitotic kinesins and mitotic kinases. However, these agents have thus far been disappointing in the clinic, further highlighting our inability to identify which tumour genotypes to target.
Following a genome-wide siRNA screen for taxol sensitizers, we recently identified the oncogenic transcription factor c-Myc as a major determinant of mitotic cell fate. We showed that Myc sensitizes cells to various antimitotics by upregulating a cluster of redundant pro-apoptotic BH3-only proteins and suppressing pro-survival Bcl-xL. Pharmacological inhibition of Bcl-xL restores apoptosis in Myc-deficient cells, and gene expression analysis of breast cancers indicates that taxane responses correlate positively with Myc and negatively with Bcl-xL.
We are now translating these findings into a clinically relevant context to explore opportunities for biomarkers and combination therapies that could enhance traditional and 2nd generation antimitotic agents.