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

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.

Drug mechanism-of-action discovery through the integration of pharmacological and CRISPR screens

“…Understanding drug mechanism-of-action and evaluating in cellular activity is 53 challenging (Santos et al, 2017) and widespread target promiscuity contributes to low success 54 rates during drug development (Klaeger et al, 2017). For target-based drug development, a 55 detailed understanding of drug mechanism-of-action provides information about specificity 56 and undesirable off-target activity which could lead to toxicity and reduced therapeutic window 57 (Lin et al, 2019). Moreover, molecular biomarkers can be used to monitor drug activity and to 58 identify contexts in which drugs are more effective as the basis for patient stratification during 59 clinical development.…”

Small molecule inhibitors and a kinase-dead expressing mouse model demonstrate that the kinase activity of Chk1 is essential for mouse embryos and cancer cells

“…345, and this phosphorylation appears to be mediated by ATR since the ATR inhibitor VE821 ameliorated the S345 phosphorylation induced by Chk1 inhibitor ( Figure 1C). Small molecule inhibitors can potentially have off-target effects since their small size results in that they fit many pockets of proteins (24). They can also be pumped out of cells or remain inaccessible for tissues and developing embryos (25).…”

Drug GRADE: an integrated analysis of population growth and cell death reveals drug-specific and cancer subtype-specific response profiles

“…Failures in this process have contributed to issues with irreproducibility of phenotypes across experimental platforms, spurious associations in precision medicine, and misannotated mechanisms of drug action (Bruno et al, 2017;Chopra et al, 2019;Hafner et al, 2019;Haibe-Kains et al, 2013). Recent studies continue to reveal that we generally do not know how drugs function, even for drugs that are well-studied and precisely engineered (Lin et al, 2019). Traditional methods to evaluate a drug response have relied on pharmacological measures of a drug's dose-response relationship, such as the EC50 or IC50.…”