GEOTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE332586GEOGSEfalseMevalonate pathway activation in Ewing sarcoma reveals a 3D-specific synergy between statins and BCL-xL inhibitionBone sarcomas are rare and aggressive pediatric cancers with limited progress in targeted therapy development, partly due to the poor physiological relevance of conventional two-dimensional (2D) culture systems used for preclinical testing. To address this gap, we developed a standardized three-dimensional (3D) culture and drug-testing platform for Ewing sarcoma (ES) and osteosarcoma (OS) that more accurately recapitulates in vivo tumor biology. Notably, gene-expression analyses demonstrated that ES and OS spheroids transcriptionally converge toward patient tumor cell states, underscoring their physiological relevance for preclinical testing. Across 3D spheroids, bioprinted constructs, and patient-derived xenograft (PDX) cultures, we observed a consistent activation and dependency on the mevalonate pathway in ES. Leveraging this platform, we identified a selective therapeutic synergy between statins, which inhibit mevalonate pathway flux, and BCL-xL inhibitors—a vulnerability not detectable in 2D cultures. Importantly, this synergistic interaction was tumor-specific and absent in non-malignant fibroblasts, indicating a favorable therapeutic window. Together, these findings highlight the mevalonate pathway as a targetable metabolic dependency in ES and demonstrate how physiologically grounded 3D models can uncover clinically actionable treatment strategies that remain hidden in traditional 2D systems.2026/05/21GSE332586GSM9751080GSM9751081GSM9751082GSM9751102GSM9751103GSM9751104GSM9751105GSM9751106GSM9751107GSM9751108GSM9751109GSM9751083GSM9751084GSM9751085GSM9751086GSM9751087GSM9751088GSM9751100GSM9751089GSM9751101GSM9751090GSM9751091GSM9751092GSM9751093GSM9751113GSM9751114GSM9751115GSM9751094GSM9751095GSM9751096GSM9751097GSM9751098GSM9751110GSM9751099GSM9751111GSM975111220301332586Homo sapiens