{"doi":"10.7554/elife.104545.1","title":"Therapeutic benefits of maintaining CDK4/6 inhibitors and incorporating CDK2 inhibitors beyond progression in breast cancer","abstract":"Abstract The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy has revolutionized treatment for hormone receptor-positive (HR+) metastatic breast cancer. However, the emergence of resistance in most patients often leads to treatment discontinuation with no consensus on effective second-line therapies. The therapeutic benefits of maintaining CDK4/6i or incorporating CDK2 inhibitors (CDK2i) after disease progression remain unclear. Here, we demonstrate that sustained CDK4/6i therapy, either alone or combined with CDK2i, significantly suppresses the growth of drug-resistant HR+ breast cancer. Continued CDK4/6i treatment induces a non-canonical pathway for retinoblastoma protein (Rb) inactivation via post-translational degradation, resulting in diminished E2F activity and delayed G1 progression. Importantly, our data highlight that CDK2i should be combined with CDK4/6i to effectively suppress CDK2 activity and overcome resistance. We also identify cyclin E overexpression as a key driver of resistance to CDK4/6 and CDK2 inhibition. These findings provide crucial insights into overcoming resistance in HR+ breast cancer, supporting the continued use of CDK4/6i and the strategic incorporation of CDK2i to improve therapeutic outcomes.","journal":"eLife","year":2025,"id":560933,"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":0.9482,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1452885,"name":"Sungsoo Kim","orcid":"0000-0003-1870-3495","position":1,"is_corresponding":false},{"id":375762,"name":"Kibum Kim","orcid":"0000-0002-8676-7434","position":2,"is_corresponding":false},{"id":1362934,"name":"Eugene Son","orcid":null,"position":3,"is_corresponding":false},{"id":849950,"name":"Minah Kim","orcid":"0000-0003-0883-5320","position":4,"is_corresponding":false},{"id":357041,"name":"Hee Won Yang","orcid":"0000-0002-0000-8091","position":5,"is_corresponding":false},{"id":1028791,"name":"Jessica Armand","orcid":null,"position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":null,"created_at":"2026-07-19T02:55:46.921885Z","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":[]}