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Characteristics of senescent cells resistant to ABT263 and ARV825

ABSTRACT: ABT263 and ARV825 were identified as promising senolytic drugs based on our criteria. However, 20–30% of senescent cells survived treatment with these agents. To clarify why a subset of senescent cells remained resistant, we performed RNA-seq to characterize the surviving population. Several SASP factors were upregulated compared with untreated senescent cells, suggesting that incomplete senolysis may diminish therapeutic benefits and that more effective elimination of senescent cells is required. In addition, AKR1C1–3, which are involved in detoxifying reactive carbonyl species and reducing oxidative stress, were also upregulated. These results suggest that the surviving cells may overcome mitochondrial stress by preserving mitochondrial membrane potential and limiting ROS accumulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313462 | GEO | 2025/12/15

REPOSITORIES: GEO

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Project description:Cellular senescence contributes to a variety of pathologies associated with aging and is implicated as a cellular state in which cancer cells can survive treatment. Reported senolytic drug treatments act through varying molecular mechanisms, but heterogeneous efficacy across the diverse contexts of cellular senescence indicates a need for predictive biomarkers of senolytic activity. Using multi-parametric analyses of commonly reported molecular features of the senescent phenotype, we assayed a variety of models, including malignant and nonmalignant cells, using several triggers of senescence induction and found no predictive power of these traditional senescence markers to identify senolytic drug sensitivity. We sought to identify novel drug targets in senescent cells that were insensitive to frequently implemented senolytic therapies, such as Navitoclax (ABT263), using quantitative mass spectrometry to measure changes in the senescent proteome, compared to cells which acquire an acute sensitivity to ABT263 with senescence induction. Inhibition of the antioxidant GPX4 or the Bcl-2 family member MCL-1 using small molecule compounds in combination with ABT263 significantly increased the induction of apoptosis in some, but not all, previously insensitive senescent cells. We then asked if we could use BH3 profiling to measure differences in mitochondrial apoptotic priming in these models of cellular senescence and predict sensitivity to the ABT263 or the combination of dasatinib and quercetin (D+Q). We found, despite being significantly less primed for apoptosis overall, the dependence of senescent mitochondria on BCL-xL was significantly correlated to senescent cell killing by both ABT263 and D+Q, despite no significant changes in the gene or protein expression of BCL-xL. However, our data caution against broad classification of drugs as globally senolytic and instead provide impetus for context-specific senolytic targets and propose BH3 profiling as an effective predictive biomarker.

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Characteristics of senescent cells resistant to ABT263 and ARV825

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