MYC Sensitizes Cancer Cells to Antimitotic Therapies

Mitotic arrest can result in cell death in mitosis (DiM) or slippage, in which a cell survives, returning to interphase without cell division. Taxol and other antimitotic drugs are effective treatments for several cancers, but the molecular mechanisms underlying the induction of apoptosis during mitotic arrest have not been established. Topham and colleagues performed a genome-wide siRNA screen to identify candidate regulators of DiM. Among the candidate genes, depletion of MYC or its target early growth response 1 inhibited DiM and shifted cell fate in favor of slippage, suggesting that MYC sensitizes cells to apoptosis during mitotic arrest. In support of this idea, MYC inhibition resulted in reduced apoptotic responses to various antimitotic cancer therapies in nine of 12 cancer cell lines. In addition, MYC promoted postmitotic apoptosis following slippage in a p53-independent manner. Mechanistically, MYC regulated DiM by downregulating expression of the gene encoding BCL-XL, an antiapoptotic factor, and by upregulating expression of genes encoding three proapoptotic BH3-only proteins, BID, BIM, and NOXA, which functioned as redundant downstream effectors of MYC. Depletion of MYC enhanced cell survival in response to low-dose taxol, whereas inhibition of BCL-XL restored apoptosis in the absence of MYC. Conversely, MYC overexpression accelerated DiM and augmented postmitotic cell death; consistent with this finding, elevated MYC levels were correlated with improved responses to antimitotic drugs in cancer cell lines and patients. These results identify MYC as a determinant of cell fate during mitotic arrest and a potential biomarker of taxane efficacy, and suggest that inhibition of BCL-XL may be effective in combination with antimitotic agents.

Topham C, Tighe A, Ly P, Bennett A, Sloss O, Nelson L, et al. MYC is a major determinant of mitotic cell fate. Cancer Cell 2015;28:129–40.

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