{"doi":"10.1038/s43018-024-00740-1","title":"A deep learning model of tumor cell architecture elucidates response and resistance to CDK4/6 inhibitors","abstract":"Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have revolutionized breast cancer therapy. However, <50% of patients have an objective response, and nearly all patients develop resistance during therapy. To elucidate the underlying mechanisms, we constructed an interpretable deep learning model of the response to palbociclib, a CDK4/6i, based on a reference map of multiprotein assemblies in cancer. The model identifies eight core assemblies that integrate rare and common alterations across 90 genes to stratify palbociclib-sensitive versus palbociclib-resistant cell lines. Predictions translate to patients and patient-derived xenografts, whereas single-gene biomarkers do not. Most predictive assemblies can be shown by CRISPR-Cas9 genetic disruption to regulate the CDK4/6i response. Validated assemblies relate to cell-cycle control, growth factor signaling and a histone regulatory complex that we show promotes S-phase entry through the activation of the histone modifiers KAT6A and TBL1XR1 and the transcription factor RUNX1. This study enables an integrated assessment of how a tumor's genetic profile modulates CDK4/6i resistance.","journal":"Nature Cancer","year":2024,"id":418451,"datarank":0.5955437870328184,"base_score":3.970291913552122,"endowment":3.970291913552122,"self_citation_contribution":0.5955437870328184,"citation_network_contribution":0.0,"self_endowment_contribution":0.5955437870328184,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":52,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9478,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":641727,"name":"Erica Silva","orcid":"0000-0002-2359-7976","position":1,"is_corresponding":false},{"id":2178,"name":"Akshat Singhal","orcid":"0000-0001-5371-526X","position":2,"is_corresponding":false},{"id":2179,"name":"Marcus R. Kelly","orcid":"0000-0003-3670-8126","position":3,"is_corresponding":false},{"id":1036603,"name":"Kate Licon","orcid":null,"position":4,"is_corresponding":false},{"id":1206841,"name":"I. Panagiotou","orcid":null,"position":5,"is_corresponding":false},{"id":1206842,"name":"Catalina Fogg","orcid":null,"position":6,"is_corresponding":false},{"id":226441,"name":"Samson Fong","orcid":"0000-0001-6666-5222","position":7,"is_corresponding":false},{"id":226443,"name":"John J. Y. Lee","orcid":"0000-0002-7967-3384","position":8,"is_corresponding":false},{"id":1117249,"name":"Xiaoyu Zhao","orcid":"0000-0002-6081-2196","position":9,"is_corresponding":false},{"id":1002953,"name":"Robin E. Bachelder","orcid":"0000-0001-7502-2907","position":10,"is_corresponding":false},{"id":715248,"name":"Barbara A. Parker","orcid":"0000-0003-0499-1289","position":11,"is_corresponding":false},{"id":994290,"name":"Kay T. Yeung","orcid":"0000-0002-0013-7002","position":12,"is_corresponding":false},{"id":1362,"name":"Trey Ideker","orcid":"0000-0002-1708-8454","position":13,"is_corresponding":false},{"id":1206079,"name":"Sungjoon Park","orcid":"0009-0004-9965-7068","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:57:02.483590Z","pmid":"38443662","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":[]}