This study, presented by Herter et al., aimed to identify novel treatment options for relapsed neuroblastomas, which are often mesenchymal, resistant to treatment, and more prevalent in children. The researchers tested 91 pediatric cancer cell models, including patient-derived mini-tumors encompassing the range of mesenchymal to adrenergic subtypes, against 76 anti-cancer drugs. Methods included a metabolic activity assay with high-throughput ATP-based luminescence measurements, high-content confocal imaging analyzed with a Cell Profiler pipeline and machine learning based Cell Profiler Analyst classification tool, senescence assays, gene expression profiling, and zebrafish models. The machine learning imaging tools assisted in the classification of segmented and stained nuclei. The study found that mesenchymal neuroblastomas had sensitivity to MEK inhibitors, high MAPK activity, high basal lysosomal content, which increased in response to MAPKi treatment, and increased therapy-induced senescence, an arrest in the cell cycle that can rarely re-enter the cell cycle as a cancer stem cell and cause tumor relapse. By combining MEK inhibitors that targeted MAPK pathways with BCL2-family inhibitors targeting senescent cells, the study demonstrated significant synergistic impairment of mesenchymal neuroblastoma growth. Findings were validated by gene expression analysis, drug sensitivity profiling, and in vivo models. This promises a potential new treatment regimen for children with relapsed neuroblastomas that takes advantage of the additive effects of senolytic therapies to reduce the risk of cancer relapse.