Andrzejewski Slawomir, Winter Marie, Garcia Leandro Encarnacao, Akinrinmade Olusiji, Marques Francisco D M, Zacharioudakis Emmanouil, Skwarska Anna, Aguirre-Ghiso Julio, Konopleva Marina, Zheng Guangrong, Fineberg Susan, Zhou Daohong, Gavathiotis Evripidis, Wang Tao, Dhimolea Eugen
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA.
bioRxiv. 2025 Aug 25:2025.08.21.671546. doi: 10.1101/2025.08.21.671546.
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 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 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.
化疗后存活的持久性残留肿瘤细胞是治疗失败的主要原因，但其存活机制仍 largely 难以捉摸。这些癌细胞的典型特征是处于静止状态，MYC 和 MTOR 的活性受到抑制。我们观察到，MYC 抑制的持久性三阴性乳腺癌（TNBC）细胞具有代谢灵活性，并且可以响应 DNA 损伤的蒽环类药物（如阿霉素）而上调线粒体氧化磷酸化（OXPHOS）基因和呼吸功能（“OXPHOS 高”细胞状态），但对紫杉烷类药物无反应。OXPHOS 高的持久性癌细胞中线粒体生物量和呼吸功能的升高与线粒体延长和重塑相关，提示线粒体融合增加。在阿霉素持久性 OXPHOS 高的 TNBC 细胞中进行的全基因组 CRISPR 编辑筛选显示，BCL-XL 基因是这些静止肿瘤细胞中最主要的存活依赖性基因，但在未处理的增殖对应细胞中并非如此。静止的 OXPHOS 高的 TNBC 细胞对 BCL-XL 抑制剂高度敏感，但对 BCL2 和 MCL1 的抑制剂不敏感。有趣的是，在阿霉素持久性 OXPHOS 高的 TNBC 细胞中抑制 BCL-XL 会迅速消除线粒体延长和呼吸功能，随后激活 caspase 3/7 并导致细胞死亡。血小板保护蛋白水解靶向嵌合体（PROTAC）BCL-XL 降解剂 DT2216 增强了阿霉素对 TNBC 异种移植瘤的疗效，而不会诱导第一代 BCL-XL 抑制剂常见的血小板减少，支持了这种联合治疗策略的开发，用于消除蒽环类化疗后持续存在的休眠肿瘤细胞。
