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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 (\u201cOXPHOS-high\u201d 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.<\/jats:p>","DOI":"10.3390\/cells14191557","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T08:22:08Z","timestamp":1759911728000},"page":"1557","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Quiescent OXPHOS-High Triple-Negative Breast Cancer Cells That Persist After Chemotherapy Depend on BCL-XL for Survival"],"prefix":"10.3390","volume":"14","author":[{"given":"Slawomir","family":"Andrzejewski","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Cancer Dormancy Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3910-1568","authenticated-orcid":false,"given":"Marie","family":"Winter","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Cancer Dormancy Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4556-1624","authenticated-orcid":false,"given":"Leandro","family":"Encarnacao Garcia","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Cancer Dormancy Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olusiji","family":"Akinrinmade","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Cancer Dormancy Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7521-6955","authenticated-orcid":false,"given":"Francisco","family":"Madeira Marques","sequence":"additional","affiliation":[{"name":"Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Cancer Dormancy Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanouil","family":"Zacharioudakis","sequence":"additional","affiliation":[{"name":"Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Cancer Dormancy Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Skwarska","sequence":"additional","affiliation":[{"name":"Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Aguirre-Ghiso","sequence":"additional","affiliation":[{"name":"Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Cancer Dormancy Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Department of Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Ruth L. and David S. 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