Senolysis by ABT-263 is associated with inherent apoptotic dependence of cancer cells derived from the non-senescent state
Jochems, F. Baltira, C. MacDonald, J. A. Daniels, V. Mathur, A. de Gooijer, M. C. van Tellingen, O. Letai, A. Bernards, R.
Jochems, F.
Baltira, C.
MacDonald, J. A.
Daniels, V.
Mathur, A.
de Gooijer, M. C.
van Tellingen, O.
Letai, A.
Bernards, R.
Abstract
Cellular senescence is a stress response that cells can employ to resist cell death. Senescent cells rely on anti-apoptotic signaling for their survival, which can be targeted by senolytic agents, like the BCL-XL, BCL-2, BCL-W inhibitor ABT-263. However, the response to ABT-263 of senescent cancer cells ranges from highly sensitive to refractory. Using BH3 profiling, we identify here apoptotic blocks in cancer cells that are resistant to this senolytic treatment and discover a correlation between mitochondrial apoptotic priming and cellular sensitivity to ABT-263 in senescence. Intriguingly, ABT-263 sensitivity correlates with overall mitochondrial apoptotic priming, not only in senescence but also in the parental state. Moreover, we confirm that ABT-263 exposure increases dependency on MCL-1, which is most enhanced in ABT-263 sensitive cells. ABT-263 resistant cells however upregulate MCL-1, while sensitive cells exhibit low levels of this anti-apoptotic protein. Overall, our data indicate that the response of senescent cells to ABT-263 is predetermined by the mitochondrial apoptotic priming state of the parental cells, which could serve as a predictive biomarker for response to senolytic therapy.
Description
Date
2025
Publisher
Collections
Keywords
Type
Article
Citation
Jochems F, Baltira C, MacDonald JA, Daniels V, Mathur A, de Gooijer MC, et al. Senolysis by ABT-263 is associated with inherent apoptotic dependence of cancer cells derived from the non-senescent state. Cell death and differentiation. 2025 May;32(5):855-65. PubMed PMID: 39706991. Pubmed Central PMCID: PMC12089325 at Agendia Inc., and board member of Lixte Biotechnology Holdings, Inc. Epub 2024/12/21. eng.