Abstract Therapy-induced Senescence (TIS) can potentially influence breast cancer treatment outcomes, in part by contributing to disease recurrence; hence, the utilization of senescence-eliminating agents (i.e., senolytics) is considered as a possibly adjuvant to both antitumor drugs and radiation. However, one of the most effective senolytic agents, navitoclax (ABT-263), is limited by its associated toxicities of thrombocytopenia and neutropenia. In contrast, venetoclax (ABT-199) is currently considered standard of care in CLL and AML. This study compared the senolytic potential of the BH3 mimetics, navitoclax and venetoclax, in targeting doxorubicin-induced senescence in two models of triple negative breast cancer (4T1 and E0771 cells). Senescence was cytochemically confirmed via Senescence-associated β-galactosidase upregulation (and quantified by flow cytometry), TP53 and p21Cip1 (CDKN1A) induction, and the senescence-associated secretory phenotype (SASP) expression (using qRT-PCR). Cell viability and the percentage of apoptotic cells were determined using MTT and Annexin V/7AAD assays, respectively. Responses differed in the two cell lines. Both navitoclax and venetoclax were effective as apparent senolytics in the E0771 cells. In contrast, only navitoclax was effective against the 4T1 cells. The in vitro findings in E0771 cells were validated through studies conducted in vivo in immunocompetent mice implanted with E0771-derived tumors where both drugs reduced tumor progression in sequential combination with doxorubicin. These findings suggest that administration of venetoclax has the potential to enhance suppression of chemotherapy-induced senescent cancer cells, and that it may not be necessary to use senolytic agents that target Bcl-xL. However, given the variable outcomes in the two triple negative breast tumor cell lines, it becomes incumbent to identify the factors that confer susceptibility to Bcl-2 targeting senolytics in anticipation of their potential utilization in the clinic for combination therapy in solid tumors. Citation Format: H. As Sobeai, K. Alhazzani, M. Almutairi, T. Saleh, B. Al-Ramadi, D. Gewirtz, H. Harada, M. Alotaibi. Differential Responses to the Senolytic Activities of Navitoclax and Venetoclax in Murine Models of Triple Negative Breast Cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-12-27.
Sobeai et al. (Tue,) studied this question.