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Suppression of INK4 expression or its binding to CDK6 restores CDK4/6i sensitivity. To overcome this constraint, we developed bifunctional degraders conjugating palbociclib with E3 ligands. Two resulting lead compounds potently degraded CDK4/6, leading to substantial antitumor effects <i>in vivo</i>, demonstrating the promising therapeutic potential for retargeting CDK4/6 despite CDK4/6i resistance.</p>Significance:<p>CDK4/6 kinase activation represents a common mechanism by which oncogenic signaling induces proliferation and is potentially targetable by ATP competitive inhibitors. We identify a CDK6–INK4 complex that is resilient to current-generation inhibitors and develop a new strategy for more effective inhibition of CDK4/6 kinases.</p><p><i>This article is highlighted in the In This Issue feature, p. 275</i></p></div>","journal":null,"year":null,"id":646608,"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":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":347440,"name":"Baishan Jiang","orcid":"0000-0001-6796-9500","position":1,"is_corresponding":false},{"id":626245,"name":"Jiaye Guo","orcid":"0000-0001-7439-1479","position":2,"is_corresponding":false},{"id":586077,"name":"Hong Shao","orcid":"0000-0002-4353-5609","position":3,"is_corresponding":false},{"id":16050,"name":"Isabella Del Priore","orcid":"0000-0002-9665-1101","position":4,"is_corresponding":false},{"id":451224,"name":"Qing Chang","orcid":"0000-0001-7406-8479","position":5,"is_corresponding":false},{"id":626246,"name":"Rei Kudo","orcid":"0000-0003-0702-5828","position":6,"is_corresponding":false},{"id":626247,"name":"Zhiqiang Li","orcid":"0000-0002-2768-5332","position":7,"is_corresponding":false},{"id":90747,"name":"Pedram Razavi","orcid":"0000-0003-4236-0576","position":8,"is_corresponding":false},{"id":618847,"name":"Bo Liu","orcid":"0000-0002-5008-296X","position":9,"is_corresponding":false},{"id":626248,"name":"Andrew S. 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Mechanistically, we demonstrate CDK6 causes resistance by inducing and binding CDK inhibitor INK4 proteins (e.g., p18<sup>INK4C</sup>). <i>In vitro</i> binding and kinase assays together with physical modeling reveal that the p18<sup>INK4C</sup>–cyclin D–CDK6 complex occludes CDK4/6i binding while only weakly suppressing ATP binding. Suppression of INK4 expression or its binding to CDK6 restores CDK4/6i sensitivity. To overcome this constraint, we developed bifunctional degraders conjugating palbociclib with E3 ligands. Two resulting lead compounds potently degraded CDK4/6, leading to substantial antitumor effects <i>in vivo</i>, demonstrating the promising therapeutic potential for retargeting CDK4/6 despite CDK4/6i resistance.</p>Significance:<p>CDK4/6 kinase activation represents a common mechanism by which oncogenic signaling induces proliferation and is potentially targetable by ATP competitive inhibitors. We identify a CDK6–INK4 complex that is resilient to current-generation inhibitors and develop a new strategy for more effective inhibition of CDK4/6 kinases.</p><p><i>This article is highlighted in the In This Issue feature, p. 275</i></p></div>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19767382","pmcid":null,"openalex_id":"https://openalex.org/W4362546411","authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"http://dx.doi.org/10.1158/2159-8290.c.6549415.v1","host_type":""},{"url":"http://dx.doi.org/10.1158/2159-8290.c.6549415.v1","host_type":""}],"fields_of_study":["Advanced Breast Cancer Therapies","Neuroendocrine Tumor Research Advances","Lung Cancer Research Studies"],"mesh_terms":[],"keywords":["Cyclin-dependent kinase 6","Cyclin-dependent kinase","Kinase","Palbociclib","Cyclin-dependent kinase 4","Cancer research","Biology","Retinoblastoma protein","Molecular biology","Cell cycle","Cyclin-dependent kinase 2","Cell biology","Cancer","Biochemistry","Protein kinase A","Breast cancer","Cell","Genetics","Metastatic breast cancer"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-09T13:59:42.618867Z","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":[]}