ArticleScience translational medicine2019
Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials.
Article in Science translational medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 396 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
396 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Signaling pathway mechanisms in pancreatic ductal adenocarcinoma tumor microenvironment and emerging targeting strategies for improved prognosis.Oncology reviews · 2026Pooled it
- PROTACs in cancer therapy: targeted degradation of GPX4, PARP and epigenetic regulators.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Chromosomal instability in cancer: sources, consequences and new therapeutic opportunities.Signal transduction and targeted therapy · 2026Review
- Harnessing endogenous carbon monoxide for cancer-selective drug synthesis.Nature communications · 2026Article
- Multiple Myeloma-Derived Cellular Lipids Enhance Targeting and Efficacy of Nanoliposome Formulations In Vitro.International journal of molecular sciences · 2026Article
- Cyclins and Cyclin-Dependent Kinases: Structure, Biological Functions, and Innovative Targeting Strategies in Cancer.MedComm · 2026Review
- GW4869 Depletes Macrophages and Increases Number of Extracellular Vesicles in Murine Peritoneal Cavity Fluid.Journal of extracellular biology · 2026Article
- Targeting CDKs in the RNAPII transcription cycle.Nature reviews. Drug discovery · 2026Review
- [Prediction and verification of therapeutic drugs for triple-negative breast cancer using a knowledge graph-based drug repurposing model].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2026Article
- Colonoid-Based Transcriptomics Reveals Conserved and Model-Specific Mechanisms of Doxorubicin-Induced Intestinal Toxicity.International journal of molecular sciences · 2026Article
- AntagomiR-155 hitchhiking on biomimetic yeast microcapsules alleviate atherosclerosis by inhibiting M1-like macrophages.Materials today. Bio · 2026Article
- Cell painting and thermal proteome profiling for inference of drug targets and mechanism of action.Molecular systems biology · 2026Article
- Contemporary design of small-molecule kinase modulators: orthosteric, allosteric and induced-proximity strategies.Nature reviews. Drug discovery · 2026Review
- Structural basis of the regulation by CDK11 kinase of early spliceosome activation and evidence for its proofreading by DHX15 helicase.Nature communications · 2026Article
- The competition between splicing and 3' processing shapes the human transcriptome.Genes & development · 2026Article
- Drugging non-canonical kinases in cancer therapeutics: Molecular targets, underlying mechanisms and small-molecule inhibitors.Acta pharmaceutica Sinica. B · 2026Review
- Virus-like particles in cancer immunotherapy: bridging human and veterinary medicine through one health.Journal of nanobiotechnology · 2026Review
- Small-molecule inhibitors of the protein kinase DYRK as potential therapeutic candidates in cancer.Cell chemical biology · 2026Article
- Overcoming chemotherapy resistance in diffuse large B-cell lymphoma using multifunctional nanocarriers: current advances and clinical challenges.Discover nano · 2026Review
- SF3B1 phosphorylation is an evolutionarily conserved step in spliceosome activation carried out by the divergent, OTS964-insensitive kinase CRK9 in trypanosomes.Nucleic acids research · 2026Article
336 more citing papers are in PubMed but not listed here.
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13 authors.
Funding
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.