Faculty, Staff and Student Publications
Language
English
Publication Date
10-8-2025
Journal
Cells
DOI
10.3390/cells14191557
PMID
41090785
PMCID
PMC12524137
PubMedCentral® Posted Date
10-8-2025
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Humans, Triple Negative Breast Neoplasms, bcl-X Protein, Oxidative Phosphorylation, Female, Cell Line, Tumor, Animals, Mitochondria, Cell Survival, Mice, Doxorubicin, Xenograft Model Antitumor Assays, Apoptosis
Published Open-Access
yes
Recommended Citation
Andrzejewski, Slawomir; Winter, Marie; Encarnacao Garcia, Leandro; et al., "Quiescent OXPHOS-High Triple-Negative Breast Cancer Cells That Persist After Chemotherapy Depend on BCL-XL for Survival" (2025). Faculty, Staff and Student Publications. 6750.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6750
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