biostudies-literatureLopez JMinistry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)Generalitat de Catalunya (Government of Catalonia)91https://www.ebi.ac.uk/biostudies/studies/S-EPMC11889205biostudies-literatureUnknown11(1)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-deficieCell death discoveryMitochondrial priming and response to BH3 mimetics in "one-two punch" senogenic-senolytic strategies.PMC11889205CP20/00003PI22/00297CM22/002762022 INV-1 00001Teixidor ECuyas ELopez-Bonet EMenendez JAMartin-Castillo BLopez JAlarcon TVerdura SLupu RLlop-Hernandez ASardanyes JBosch-Barrera JMartinez-Balibrea ESerrano-Hervas EfalseMitochondrial priming and response to BH3 mimetics in "one-two punch" senogenic-senolytic strategies.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-deficie2025-01-01T00:00:00Z2025 Mar2025-04-18T17:28:19.737Z2025-04-07T04:58:42.991ZS-EPMC118892054005533610.1038/s41420-025-02379-y