Abstract
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.
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Acknowledgements
The authors wish to acknowledge flow cytometry support from Dorota Wyczechowska, PhD.
Funding
This study was supported by the Department of Defense Breast Cancer Research Program (grant number W81XWH-14-1-0216 to JGJ) and The National Center for Advancing Translational Sciences (award TL1TR003106 to AS). Content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Sciences. The Cellular Immunology and Immune Metabolism Core at the Louisiana Cancer Research Consortium is supported by a grant from the NIN/NIGMS (grant number 1P30GM114732-01).
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Shahbandi, A., Rao, S.G., Anderson, A.Y. et al. BH3 mimetics selectively eliminate chemotherapy-induced senescent cells and improve response in TP53 wild-type breast cancer. Cell Death Differ 27, 3097–3116 (2020). https://doi.org/10.1038/s41418-020-0564-6
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DOI: https://doi.org/10.1038/s41418-020-0564-6
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