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.

Parasitic nematodes infect over one quarter of the population worldwide, causing morbidity in over one billion people. Current anthelmintic drugs are beginning to lose effectiveness due to the presence of resistant strains. We are interested in the role of neuropeptides, which regulate behaviors in all organisms, as another possible target for anthelmintic drugs. FMRFamide-related peptides (FaRPs) are a family of neuropeptides that are conserved throughout the animal kingdom. In particular, nematodes contain the largest family of FaRPs identified thus far and many of these FaRPs are identical among different nematode species; FaRPs in nematodes are collectively referred to as FLPs (FMRFamide-like peptides). However, little is known about the function of these FLPs. We are using the non-parasitic nematode Caenorhabditis elegans as a model for examining FLPs in nematodes. C. elegans contains at least 31 flp genes that encode 72 potential FLPs. Among the flp genes, flp-1 is one of the few that is universally found in nematodes. FLP-1 neuropeptides were previously reported to be involved in sensory and motor functions. However, previous alleles of flp-1 also disrupted a neighboring gene, daf-10. To understand the phenotypes of flp-1, new alleles that specifically disrupt flp-1 were characterized. The previously reported locomotory and egg-laying defects were found to be due to loss of flp-1, while the osmolarity defect is due to loss of daf-10. In addition, loss of flp-1 and daf-10 both cause several phenotypes that increase in severity in the double mutants by disrupting different neurons in the neural circuits.

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