{"doi":"10.1073/pnas.2221448120","title":"Cooperative regulation of coupled oncoprotein synthesis and stability in triple-negative breast cancer by EGFR and CDK12/13","abstract":"Evidence has long suggested that epidermal growth factor receptor (EGFR) may play a prominent role in triple-negative breast cancer (TNBC) pathogenesis, but clinical trials of EGFR inhibitors have yielded disappointing results. Using a candidate drug screen, we identified that inhibition of cyclin-dependent kinases 12 and 13 (CDK12/13) dramatically sensitizes diverse models of TNBC to EGFR blockade. This combination therapy drives cell death through the 4E-BP1-dependent suppression of the translation and translation-linked turnover of driver oncoproteins, including MYC. A genome-wide CRISPR/Cas9 screen identified the CCR4-NOT complex as a major determinant of sensitivity to the combination therapy whose loss renders 4E-BP1 unresponsive to drug-induced dephosphorylation, thereby rescuing MYC translational suppression and promoting MYC stability. The central roles of CCR4-NOT and 4E-BP1 in response to the combination therapy were further underscored by the observation of CNOT1 loss and rescue of 4E-BP1 phosphorylation in TNBC cells that naturally evolved therapy resistance. Thus, pharmacological inhibition of CDK12/13 reveals a long-proposed EGFR dependence in TNBC that functions through the cooperative regulation of translation-coupled oncoprotein stability.","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":340177,"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":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1074495,"name":"Natalia Sutiman","orcid":"0009-0007-5713-5909","position":1,"is_corresponding":false},{"id":814062,"name":"Xinyue Deng","orcid":"0000-0002-6641-8317","position":2,"is_corresponding":false},{"id":345378,"name":"Annie Liu","orcid":"0000-0003-0729-4390","position":3,"is_corresponding":false},{"id":869969,"name":"Christian Cerda-Smith","orcid":"0000-0001-8123-5300","position":4,"is_corresponding":false},{"id":867778,"name":"Haley M. Hutchinson","orcid":"0000-0002-8181-6022","position":5,"is_corresponding":false},{"id":1075163,"name":"Holly Kim","orcid":null,"position":6,"is_corresponding":false},{"id":629900,"name":"Luke C. Bartelt","orcid":"0000-0001-8731-3680","position":7,"is_corresponding":false},{"id":667917,"name":"Qiang Chen","orcid":"0000-0002-6795-1578","position":8,"is_corresponding":false},{"id":303894,"name":"Alejandro Barrera","orcid":"0000-0001-9244-9822","position":9,"is_corresponding":false},{"id":725444,"name":"Jiaxing Lin","orcid":"0000-0003-3193-5522","position":10,"is_corresponding":false},{"id":870609,"name":"Zhecheng Sheng","orcid":null,"position":11,"is_corresponding":false},{"id":686236,"name":"Ian C. McDowell","orcid":"0000-0001-5811-1297","position":12,"is_corresponding":false},{"id":27827,"name":"Timothy E. Reddy","orcid":"0000-0002-7629-061X","position":13,"is_corresponding":false},{"id":395501,"name":"Christopher V. Nicchitta","orcid":"0000-0001-7889-1155","position":14,"is_corresponding":false},{"id":288305,"name":"Kris C. Wood","orcid":"0000-0002-5887-2253","position":15,"is_corresponding":false},{"id":814060,"name":"Hazel X. Ang","orcid":"0000-0002-4194-7204","position":0,"is_corresponding":true}],"reference_count":100,"raw_metadata":null,"created_at":"2026-07-19T01:10:54.145367Z","pmid":"37695916","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":[]}