Editors' ChoiceCANCER THERAPEUTICS

Speed kills

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Science Translational Medicine  20 Apr 2016:
Vol. 8, Issue 335, pp. 335ec63
DOI: 10.1126/scitranslmed.aaf7822

Advances in computational biology and massively parallel sequencing now routinely enable rapid, deep tumor profiling. Concomitant analytical advances have streamlined the clinical identification of genomic alterations that drive tumor development. Such information can guide therapeutic regimens in the clinic. Yet, it remains unclear why even the most effective drugs can fail to eliminate all isogenic tumor cells. Now, Paek et al. show that it is not the absolute level of the p53 tumor suppressor protein in a cell that determines whether it will be eliminated by DNA-damaging agents such as cisplatin but, rather, the speed with which that level is achieved after treatment.

Chemotherapeutic drugs such as cisplatin kill rapidly dividing cancer cells by crosslinking DNA and inducing a DNA-damage response that, in turn, initiates apoptosis. The transcription factor p53 plays a key role in controlling this behavior. Variability in the levels or activity of p53 across individual tumor cells might explain why some escape apoptosis and survive, but this hypothesis had yet to be explored.

The authors performed live-cell imaging of fluorescently labeled p53 in a human colon cancer cell line and analyzed p53 trajectories in hundreds of single cells in response to cisplatin and related chemotherapeutics. Their data showed that, early after treatment, cells reaching a nearly fixed threshold level of p53 would undergo apoptosis. Yet, for cells in which p53 did not achieve this threshold rapidly, a higher level of p53 was required to induce the same. By performing chemical and genetic perturbations, they further demonstrated that this shift is due to up-regulation of inhibitors of apoptosis proteins (IAP), including cIAP2 and XIAP, which are induced by p53, and cIAP1 and ML-IAP, which are not. Studies in caspase 8 knockout cells revealed that cIAP1 and cIAP2 counteract caspase 8−dependent apoptosis induced by DNA-damaging agents, whereas XIAP and ML-IAP block a caspase 8−independent mechanism.

Overall, the authors’ findings suggest that coupling chemotherapeutics such as cisplatin with agents that stabilize p53 or accelerate its accumulation might increase therapeutic efficacy. Further work is needed to test the utility of these strategies in primary tumors, as well as to identify the factors and dynamics that inform responses to other distinct classes of cancer drugs. Nevertheless, this work beautifully demonstrates how directly profiling tumor cell heterogeneity can help elucidate the drivers of cellular phenotypes and thus improve therapeutic strategies.

A. L. Paek et al., Cell-to-cell variation in p53 dynamics leads to fractional killing. Cell 10.1016/j.cell.2016.03.025 (2016). [Abstract]

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