Editors' ChoiceCancer

Predicting drug resistance before it occurs

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Science Translational Medicine  30 Sep 2015:
Vol. 7, Issue 307, pp. 307ec166
DOI: 10.1126/scitranslmed.aad3625

As our understanding of the molecular mechanism of cancer deepens, an ever-increasing array of therapeutic targets emerges. One such target is the Mps1/TTK dual-specificity kinase, which regulates the mitotic checkpoint and is nonredundant for cell survival. As a kinase, it is a particularly attractive therapeutic target, and several specific small molecule inhibitors of Mps1/TTK have already been developed in preclinical models. As promising as preclinical results might be, however, the reality of new drug targets and their inhibitors is that they rarely work in patients. The reasons for this are manifold and include existence or emergence of drug resistance in tumors. Resistance mechanisms are often poorly understood, and rarely known before drugs are tested in patients.

In this context, the work of Koch and colleagues on resistance to Mps1/TTK inhibitors in preclinical models is a breath of fresh air. In a series of experiments, they revealed possible mechanisms of resistance to Mps1/TTK inhibitors, which will inform future development of these drugs. After demonstrating that drug resistance to Mps1/TTK inhibitors can arise in vitro, the researchers identified specific mutations in the Mps1/TTK gene in some of the resistant clones. The resistance mechanism of these mutations was not, as one may have predicted, an increase in Mps1/TTK activity. Rather, each of the mutations mediated resistance by interfering with binding of the inhibitors to Mps1/TTK. Thus, modifying the chemical structure of the inhibitors to make them capable of binding to mutant Mps1/TTK may be a strategy to combat resistance before it occurs.

Although it is focused on a very specific therapeutic target, this study illustrates an elegant strategy for finding weaknesses in small molecule inhibitors before they are taken to the bedside. Whether studying preclinical drugs in this much detail will ultimately translate into patient benefits remains to be seen. However, given the high failure rate of targeted therapies, it would appear to be a worthwhile endeavour to systematically apply the experimental approach of Koch et al. to new targeted inhibitors.

A. Koch et al., Molecular basis underlying resistance to Mps1/TTK inhibitors. Oncogene 10.1038/onc.2015.319 (2015). [Full Text]

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