{"doi":"10.1016/j.celrep.2019.02.023","title":"MicroRNA-Mediated Suppression of the TGF-β Pathway Confers Transmissible and Reversible CDK4/6 Inhibitor Resistance","abstract":null,"journal":"Cell Reports","year":2019,"id":607691,"datarank":0.7423139835567254,"base_score":4.948759890378168,"endowment":4.948759890378168,"self_citation_contribution":0.7423139835567254,"citation_network_contribution":0.0,"self_endowment_contribution":0.7423139835567254,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":140,"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":3745,"name":"Seth A. Wander","orcid":"0000-0002-4127-4708","position":1,"is_corresponding":false},{"id":1560478,"name":"Tanvi Visal","orcid":null,"position":2,"is_corresponding":false},{"id":3754,"name":"Nikhil Wagle","orcid":"0000-0003-3332-9438","position":3,"is_corresponding":false},{"id":230281,"name":"Geoffrey I. Shapiro","orcid":"0000-0002-3331-4095","position":4,"is_corresponding":false},{"id":1560475,"name":"Liam Cornell","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"MicroRNA-Mediated Suppression of the TGF-β Pathway Confers Transmissible and Reversible CDK4/6 Inhibitor Resistance","abstract":"CDK4/6 inhibition is now part of the standard armamentarium for patients with estrogen receptor-positive (ER + ) breast cancer, so that defining mechanisms of resistance is a pressing issue. Here, we identify increased CDK6 expression as a key determinant of acquired resistance after palbociclib treatment in ER + breast cancer cells. CDK6 expression is critical for cellular survival during palbociclib exposure. The increased CDK6 expression observed in resistant cells is dependent on TGF-β pathway suppression via miR-432-5p expression. Exosomal miR-432-5p expression mediates the transfer of the resistance phenotype between neighboring cell populations. Levels of miR-432-5p are higher in primary breast cancers demonstrating CDK4/6 resistance compared to those that are sensitive. These data are further confirmed in pre-treatment and post-progression biopsies from a parotid cancer patient who had responded to ribociclib, demonstrating the clinical relevance of this mechanism. Finally, the CDK4/6 inhibitor resistance phenotype is reversible in vitro and in vivo by a prolonged drug holiday.","is_dataset_classified":null,"base_score":4.948759890378168,"endowment":4.948759890378168,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"30840889","pmcid":"PMC6449498","openalex_id":"https://openalex.org/W2918928681","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"P50 CA168504","title":null},{"funder_name":"American Association for Cancer Research","grant_id":"1620-38-WAGL","title":null},{"funder_name":"NCI NIH HHS","grant_id":"T32 CA009172","title":null},{"funder_name":"National Institutes of Health","grant_id":"5T32CA009172-21","title":"GRADUATE TRAINING IN CANCER RESEARCH"},{"funder_name":"National Institutes of Health","grant_id":"5P50CA168504-03","title":"Overcoming Resistance to Standard HER2-Directed Therapies for Breast Cancer"},{"funder_name":"Cancer Couch Foundation","grant_id":"","title":null},{"funder_name":"V Foundation for Cancer Research","grant_id":"","title":null},{"funder_name":"Dana-Farber/Harvard Cancer Center","grant_id":"","title":null},{"funder_name":"American Society of Clinical Oncology","grant_id":"","title":null},{"funder_name":"Dana-Farber Cancer Institute","grant_id":"","title":null}],"total_grants":10,"fwci":11.7942,"citation_percentile":0.99092039,"influential_citations":0,"citation_trend":[{"year":2019,"count":6},{"year":2020,"count":23},{"year":2021,"count":27},{"year":2022,"count":22},{"year":2023,"count":24},{"year":2024,"count":20},{"year":2025,"count":15},{"year":2026,"count":3}],"oa_status":"gold","license":"cc-by-nc-nd","oa_locations":[{"url":"http://www.cell.com/article/S2211124719301937/pdf","host_type":"journal"},{"url":"http://www.cell.com/article/S2211124719301937/pdf","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S2211124719301937?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S2211124719301937?httpAccept=text/plain","host_type":"publisher"},{"url":"https://doi.org/10.1016/j.celrep.2019.02.023","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/30840889","host_type":"repository"},{"url":"https://doaj.org/article/8c7789aac5954e35aa49b5c70d17ceaa","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/6449498","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC6449498","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC6449498?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1016/j.celrep.2019.02.023","host_type":""},{"url":"https://dx.doi.org/10.1016/j.celrep.2019.02.023","host_type":""}],"fields_of_study":["Advanced Breast Cancer Therapies","Cancer-related Molecular Pathways","Lung Cancer Research Studies","0301 basic medicine","0303 health sciences","03 medical and health sciences","Animals","Cyclin-Dependent Kinase 4","Cyclin-Dependent Kinase 6","Humans","MicroRNAs","Transforming Growth Factor beta"],"mesh_terms":["Animals","Humans","Transforming Growth Factor beta","MicroRNAs","Cyclin-Dependent Kinase 4","Cyclin-Dependent Kinase 6"],"keywords":["Palbociclib","Cyclin-dependent kinase 6","Cancer research","Breast cancer","microRNA","Estrogen receptor","Signal transduction","Cancer","Biology","Medicine","Phenotype","Cell cycle","Internal medicine","Cyclin-dependent kinase","Cell biology","Metastatic breast cancer","Gene","Genetics","Drug resistance","Smad4","TGF-β","Targeted Therapy","Exosomes","Cdk6","Ribociclib","MicroRNAs","QH301-705.5","Transforming Growth Factor beta","Animals","Cyclin-Dependent Kinase 4","Humans","Biology (General)","Article"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. Good health"},{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"geo"},{"name":"gen"},{"name":"nct"},{"name":"doi"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-30T06:50:24.816869Z","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":[]}