Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials.

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.

Exposure to aged crumb rubber reduces survival time during a stress test in earthworms (Eisenia fetida).

Solid waste management struggles with the sustainable disposal of used tires. One solution involves shredding used tires into crumb rubber and using the material as infill for artificial turf. However, crumb rubber contains hydrocarbons, organic compounds, and heavy metals, and it travels into the environment. Earthworms living in soil contaminated with virgin crumb rubber gained 14% less body weight than did earthworms living in uncontaminated soil, but the impact of aged crumb rubber on the earthworms is unknown. Since many athletic fields contain aged crumb rubber, we compared the body weight, survivorship, and longevity in heat and light stress for earthworms living in clean topsoil to those living in topsoil contaminated with aged crumb rubber. We also characterized levels of metals, nutrients, and micronutrients of both soil treatments and compared those to published values for soil contaminated with virgin crumb rubber. Consistent with earlier research, we found that contaminated soil did not inhibit microbial respiration rates. Aged crumb rubber, like new crumb rubber, had high levels of zinc. However, while exposure to aged crumb rubber did not reduce earthworm body weight as did exposure to new crumb rubber, exposure to aged crumb rubber reduced earthworm survival time during a stress test by a statistically significant 38 min (16.2%) relative to the survival time for worms that had lived in clean soil. Aged crumb rubber and new crumb rubber appear to pose similar toxic risks to earthworms. This study suggests an environmental cost associated with the current tire-recycling solution.

The response of earthworms (Eisenia fetida) and soil microbes to the crumb rubber material used in artificial turf fields.

Municipalities have been replacing grass fields with artificial turf, which uses crumb rubber infill made from recycled tires. Crumb rubber contains hydrocarbons, organic compounds, and heavy metals. Water runoff from crumb rubber fields contains heavy metals. These components can damage the environment. We contaminated topsoil with new crumb rubber and measured its impact on earthworms and soil microbes. Specifically, we compared soil microbe activity and earthworm health, survivorship, and longevity in heat and light stress under two soil regimes: clean topsoil and clean topsoil contaminated with crumb rubber. We then characterized levels of metals, nutrients, and micronutrients of both soil treatments and compared those to published New York soil background levels and to levels set by the New York State Department of Environmental Conservation (DEC) as remediation goals. We found that: 1) contaminated soil did not inhibit microbial respiration rates, 2) earthworm survivorship was not impacted by exposure to contaminated soil, 3) earthworms' ability to cope with heat and light stress remained unchanged after living in contaminated soil, but 4) earthworms living in contaminated soil gained 14% less body weight than did earthworms living in uncontaminated soil. We also found that, with the exception of zinc, heavy metals in our contaminated soil did not exceed the background levels found throughout New York State or the remediation targets set by the DEC.