Comparative Drug Response Profiling in Neuroblastoma Cell Lines and Patient‐Derived Tumor Organoids

ABSTRACT High‐risk neuroblastoma remains a leading cause of pediatric cancer mortality, and improved preclinical models are needed to guide therapeutic developments. We screened seven high‐risk neuroblastoma cell lines and three patient‐derived tumor organoids with 528 compounds alongside bone marrow controls, and compared them with external datasets. Unsupervised clustering of drug response clearly separated two‐dimensional (2D) and three‐dimensional (3D) models, with 3D models showing more coherent responses and overall higher drug sensitivity. Mitotic and DNA‐damage pathways emerged as key vulnerabilities, and standard‐of‐care compounds, including doxorubicin, etoposide, and topotecan, were more active in 3D than 2D. This work highlights the potential of 3Dmodels as useful tools for therapy prioritization in neuroblastoma.