{"doi":"10.3410/f.736585207.793570659","title":"Faculty Opinions recommendation of Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials.","abstract":"97% of drug-indication pairs that are tested in clinical trials in oncology never advance to receive FDA 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 wellunderstood.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 RNAi and small-molecule inhibitors -the proteins ostensibly targeted by these drugs are non-essential 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 discovered that the mischaracterized anti-cancer agent OTS964 is actually a potent inhibitor of the cyclindependent 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. One-sentence summary:CRISPR reveals that many cancer drug targets are dispensable for cell proliferation and identifies CDK11 as the target of one mischaracterized agent.","journal":"Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature","year":2020,"id":134002,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.959,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":368807,"name":"Karen S. Anderson","orcid":"0000-0003-3433-0780","position":0,"is_corresponding":true}],"reference_count":204,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:16:20.998822Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}