{"doi":"10.3390/cells14191557","title":"Quiescent OXPHOS-High Triple-Negative Breast Cancer Cells That Persist After Chemotherapy Depend on BCL-XL for Survival","abstract":"The persistent residual tumor cells that survive after chemotherapy are a major cause of treatment failure, but their survival mechanisms remain largely elusive. These cancer cells are typically characterized by a quiescent state with suppressed activity of MYC and MTOR. We observed that the MYC-suppressed persistent triple-negative breast cancer (TNBC) cells are metabolically flexible and can upregulate mitochondrial oxidative phosphorylation (OXPHOS) genes and respiratory function (\"OXPHOS-high\" cell state) in response to DNA-damaging anthracyclines such as doxorubicin, but not to taxanes. The elevated biomass and respiratory function of mitochondria in OXPHOS-high persistent cancer cells were associated with mitochondrial elongation and remodeling, suggestive of increased mitochondrial fusion. A genome-wide CRISPR editing screen in doxorubicin-persistent OXPHOS-high TNBC cells revealed the BCL-XL gene as the top survival dependency in these quiescent tumor cells, but not in their untreated proliferating counterparts. Quiescent OXPHOS-high TNBC cells were highly sensitive to BCL-XL inhibitors, but not to inhibitors of BCL2 and MCL1. Interestingly, inhibition of BCL-XL in doxorubicin-persistent OXPHOS-high TNBC cells rapidly abrogated mitochondrial elongation and respiratory function, followed by caspase 3/7 activation and cell death. The platelet-sparing proteolysis-targeted chimera (PROTAC) BCL-XL degrader DT2216 enhanced the efficacy of doxorubicin against TNBC xenografts in vivo without induction of thrombocytopenia that is often observed with the first-generation BCL-XL inhibitors, supporting the development of this combinatorial treatment strategy for eliminating dormant tumor cells that persist after treatment with anthracycline-based chemotherapy.","journal":"Cells","year":2025,"id":547500,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9534,"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":1439876,"name":"Marie Winter","orcid":"0000-0002-3910-1568","position":1,"is_corresponding":false},{"id":1439877,"name":"Leandro Encarnação Garcia","orcid":"0000-0002-4556-1624","position":2,"is_corresponding":false},{"id":1440366,"name":"Olusiji Akinrinmade","orcid":null,"position":3,"is_corresponding":false},{"id":1202793,"name":"Francisco Madeira Marques","orcid":"0000-0001-7521-6955","position":4,"is_corresponding":false},{"id":292607,"name":"Emmanouil Zacharioudakis","orcid":"0000-0003-2781-9553","position":5,"is_corresponding":false},{"id":858758,"name":"Anna Skwarska","orcid":"0000-0002-0979-026X","position":6,"is_corresponding":false},{"id":105283,"name":"Julio A. Aguirre‐Ghiso","orcid":"0000-0002-6694-6507","position":7,"is_corresponding":false},{"id":18373,"name":"Marina Konopleva","orcid":"0000-0002-9347-2212","position":8,"is_corresponding":false},{"id":237880,"name":"Guangrong Zheng","orcid":"0000-0002-8106-6663","position":9,"is_corresponding":false},{"id":109019,"name":"Susan Fineberg","orcid":"0000-0002-4769-7875","position":10,"is_corresponding":false},{"id":1410882,"name":"Daohong Zhou","orcid":"0000-0002-7771-6299","position":11,"is_corresponding":false},{"id":268427,"name":"Evripidis Gavathiotis","orcid":"0000-0001-6319-8331","position":12,"is_corresponding":false},{"id":544124,"name":"Tao Wang","orcid":"0000-0001-8839-6158","position":13,"is_corresponding":false},{"id":620721,"name":"Eugen Dhimolea","orcid":"0000-0002-8445-5509","position":14,"is_corresponding":false},{"id":1439875,"name":"Sławomir Andrzejewski","orcid":"0000-0001-6599-127X","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:53:41.314800Z","pmid":"41090785","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":[]}