A probe for every protein
Science Translational Medicine 11 Sep 2019:
Vol. 11, Issue 509, eaaw8412
DOI: 10.1126/scitranslmed.aaw8412
Drugs may not do what we think they do
The majority of proposed anticancer treatments do not succeed in advancing to clinical use because of problems with efficacy or toxicity, often for unclear reasons. Lin et al. discovered that a drug candidate in clinical development was effective at killing cancer cells even when its target protein was knocked out, suggesting that its proposed mechanism of action was incorrect. The researchers then identified multiple drugs with similar problems and also discovered the correct target for one of them, suggesting that more research and more stringent methods are needed to verify the targets of potential drugs before advancing them to the clinic.
Abstract
Ninety-seven percent of drug-indication pairs that are tested in clinical trials in oncology never advance to receive U.S. Food and Drug Administration approval. While lack of efficacy and dose-limiting toxicities are the most common causes of trial failure, the reason(s) why so many new drugs encounter these problems is not well understood. Using CRISPR-Cas9 mutagenesis, we investigated a set of cancer drugs and drug targets in various stages of clinical testing. We show that—contrary to previous reports obtained predominantly with RNA interference and small-molecule inhibitors—the proteins ostensibly targeted by these drugs are nonessential for cancer cell proliferation. Moreover, the efficacy of each drug that we tested was unaffected by the loss of its putative target, indicating that these compounds kill cells via off-target effects. By applying a genetic target-deconvolution strategy, we found that the mischaracterized anticancer agent OTS964 is actually a potent inhibitor of the cyclin-dependent kinase CDK11 and that multiple cancer types are addicted to CDK11 expression. We suggest that stringent genetic validation of the mechanism of action of cancer drugs in the preclinical setting may decrease the number of therapies tested in human patients that fail to provide any clinical benefit.
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