TP53 wild-type breast tumors rarely undergo a complete pathological response after chemotherapy treatment. These patients have an extremely poor survival rate and studies show these tumors preferentially undergo senescence instead of apoptosis. These senescent cells persist after chemotherapy and secrete cytokines and chemokines comprising the senescence associated secretory phenotype, which promotes survival, proliferation, and metastasis. We hypothesized that eliminating senescent tumor cells would improve chemotherapy response and extend survival. Previous studies have shown “senolytic” agents selectively kill senescent normal cells, but their efficacy in killing chemotherapy-induced senescent cancer cells is unknown. We show that ABT-263, a BH3 mimetic that targets antiapoptotic proteins BCL2/BCL-XL/BCL-W, had no effect on proliferating cells, but rapidly and selectively induced apoptosis in a subset of chemotherapy-treated cancer cells, though sensitivity required days to develop. Low NOXA expression conferred resistance to ABT-263 in some cells, necessitating additional MCL1 inhibition. Gene editing confirmed breast cancer cells relied on BCL-XL or BCL-XL/MCL1 for survival in senescence. In a mouse model of breast cancer, ABT-263 treatment following chemotherapy led to apoptosis, greater tumor regression, and longer survival. Our results reveal cancer cells that have survived chemotherapy by entering senescence can be eliminated using BH3 mimetic drugs that target BCL-XL or BCL-XL/MCL1. These drugs could help minimize residual disease and extend survival in breast cancer patients that otherwise have a poor prognosis and are most in need of improved therapies.

TP53野生型乳腺肿瘤在化疗后很少出现完全的病理反应。这些患者的存活率极低，研究表明这些肿瘤优先经历衰老而不是细胞凋亡。这些衰老细胞在化疗后持续存在并分泌细胞因子和趋化因子，包括与衰老相关的分泌表型，促进存活、增殖和转移。我们假设消除衰老的肿瘤细胞会改善化疗反应并延长生存期。先前的研究表明，“senolytic”剂可以选择性地杀死衰老的正常细胞，但它们在杀死化疗诱导的衰老癌细胞方面的功效尚不清楚。我们表明，ABT-263，一种靶向抗凋亡蛋白 BCL2/BCL-XL/BCL-W 的 BH3 模拟物，对增殖细胞没有影响，但在化疗治疗的癌细胞亚群中快速且选择性地诱导细胞凋亡，尽管敏感性需要数天才能形成。低 NOXA 表达赋予某些细胞对 ABT-263 的抗性，需要额外的 MCL1 抑制。基因编辑证实乳腺癌细胞依赖 BCL-XL 或 BCL-XL/MCL1 在衰老过程中存活。在乳腺癌小鼠模型中，化疗后的 ABT-263 治疗导致细胞凋亡、更大的肿瘤消退和更长的生存期。我们的结果表明，可以使用靶向 BCL-XL 或 BCL-XL/MCL1 的 BH3 模拟药物消除通过进入衰老而在化疗中存活下来的癌细胞。这些药物可以帮助最大限度地减少残留疾病并延长乳腺癌患者的生存期，否则这些患者的预后很差，并且最需要改进的治疗方法。