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| Pàgina inicial > Articles > Articles publicats > Mitochondrial priming and response to BH3 mimetics in "one-two punch" senogenic-senolytic strategies |
(Universitat de Girona) (Universitat de Girona) (Institut Germans Trias i Pujol) (Universitat de Girona) (Centre de Recerca Matemàtica) (Universitat Autònoma de Barcelona. Departament de Matemàtiques) (Mayo Clinic (Rochester, Estats Units d'Amèrica)) (Institut Català d'Oncologia) (Institut Català d'Oncologia)
| Data: | 2025 |
| Resum: | A one-two punch sequential regimen of senescence-inducing agents followed by senolytic drugs has emerged as a novel therapeutic strategy in cancer. Unfortunately, cancer cells undergoing therapy-induced senescence (TIS) vary widely in their sensitivity to senotherapeutics, and companion diagnostics to predict the response of TIS cancer cells to a specific senolytic drug are lacking. Here, we hypothesized that the ability of the BH3 profiling assay to functionally measure the mitochondrial priming state-the proximity to the apoptotic threshold-and the dependencies on pro-survival BCL-2 family proteins can be exploited to inform the sensitivity of TIS cancer cells to BH3-mimetics. Replicative, mitotic, oxidative, and genotoxic forms of TIS were induced in p16 -null/ p53 -proficient, BAX -deficient, and BRCA1 -mutant cancer cells using mechanistically distinct TIS-inducing cancer therapeutics, including palbociclib, alisertib, doxorubicin, bleomycin, and olaparib. When the overall state of mitochondrial priming and competence was determined using activator peptides, the expected increase in overall mitochondrial priming was an exception rather than a generalizable feature across TIS phenotypes. A higher level of overall priming paralleled a higher sensitivity of competent TIS cancer cells to BCL-2/BCL-xL- and BCL-xL-targeted inhibitors when comparing TIS phenotypes among themselves. Unexpectedly, however, TIS cancer cells remained equally or even less overally primed than their proliferative counterparts. When sensitizing peptides were used to map dependencies on anti-apoptotic BCL-2 family proteins, competent TIS cancer cells appeared to share a dependency on BCL-xL. Furthermore, regardless of senescence-inducing therapeutic, stable/transient senescence acquisition, or genetic context, all TIS phenotypes shared a variable but significant senolytic response to the BCL-xL-selective BH3 mimetic A1331852. These findings may help to rethink the traditional assumption of the primed apoptotic landscape of TIS cancer cells. BCL-xL is a conserved anti-apoptotic effector of the TIS BCL2/BH3 interactome that can be exploited to maximize the efficacy of "one-two punch" senogenic-senolytic strategies. |
| Ajuts: | Agencia Estatal de Investigación PID2022-141955OB-I00 Generalitat de Catalunya 2022INV-100001 Instituto de Salud Carlos III PI22/00297 Agencia Estatal de Investigación RTI2018.098322-B-I00 Agencia Estatal de Investigación PID2021-127896OB-I00 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-01507 |
| Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | Cancer metabolism ; Translational research |
| Publicat a: | Cell Death Discovery, Vol. 11 (march 2025) , ISSN 2058-7716 |
