{"doi":"10.1101/2021.02.03.428245","title":"CDK4/6 inhibitors induce replication stress to cause long-term cell cycle withdrawal","abstract":"A bstract CDK4/6 inhibitors arrest the cell cycle in G1-phase. They are approved to treat breast cancer and are also undergoing clinical trials against a range of other tumour types. To facilitate these efforts, it is important to understand why a cytostatic arrest in G1 causes long-lasting effects on tumour growth. Here we demonstrate that a prolonged G1-arrest following CDK4/6 inhibition downregulates replisome components and impairs origin licencing. This causes a failure in DNA replication after release from that arrest, resulting in a p53-dependent withdrawal from the cell cycle. If p53 is absent, then cells bypass the G2-checkpoint and undergo a catastrophic mitosis resulting in excessive DNA damage. These data therefore link CDK4/6 inhibition to genotoxic stress; a phenotype that is shared by most other broad-spectrum anti-cancer drugs. This provides a rationale to predict responsive tumour types and effective combination therapies, as demonstrated by the fact that CDK4/6 inhibition induces sensitivity to chemotherapeutics that also cause replication stress.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":214306,"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":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9501,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":807748,"name":"Reece Foy","orcid":"0000-0001-5457-9853","position":1,"is_corresponding":false},{"id":549888,"name":"Brandon L. Mouery","orcid":"0000-0002-8900-3413","position":2,"is_corresponding":false},{"id":337343,"name":"Robert H. Whitaker","orcid":"0000-0002-9751-0423","position":3,"is_corresponding":false},{"id":807749,"name":"Andrea Corno","orcid":"0000-0002-7748-7561","position":4,"is_corresponding":false},{"id":501200,"name":"Christos Spanos","orcid":"0000-0002-4376-8242","position":5,"is_corresponding":false},{"id":134276,"name":"Tony Ly","orcid":"0000-0002-8650-5215","position":6,"is_corresponding":false},{"id":266825,"name":"Jeanette Gowen Cook","orcid":"0000-0003-0849-7405","position":7,"is_corresponding":false},{"id":807750,"name":"Adrian T. Saurin","orcid":"0000-0001-9317-2255","position":8,"is_corresponding":false},{"id":807747,"name":"Lisa Crozier","orcid":"0000-0002-3422-8279","position":0,"is_corresponding":true}],"reference_count":89,"raw_metadata":null,"created_at":"2026-07-18T23:52:46.604690Z","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":[]}