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

Lin, A., Giuliano, C. J., Palladino, A., John, K. M., Abramowicz, C., Yuan, M. L., Sausville, E. L., Lukow, D. A., Liu, L., Chait, A. R., Galluzzo, Z. C., Tucker, C., Sheltzer, J. M. (September 2019) Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci Transl Med, 11 (509). ISSN 1946-6234

URL: https://www.ncbi.nlm.nih.gov/pubmed/31511426
DOI: 10.1126/scitranslmed.aaw8412

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.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > CDK
diseases & disorders > cancer > drugs and therapies > chemotherapy
CSHL Authors:
Communities: CSHL labs > Sheltzer lab
Depositing User: Matthew Dunn
Date: 11 September 2019
Date Deposited: 17 Sep 2019 20:23
Last Modified: 17 Sep 2019 20:23
Related URLs:
URI: https://repository.cshl.edu/id/eprint/38411

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