Mevalonate pathway activation in Ewing sarcoma reveals a 3D-specific synergy between statins and BCL-xL inhibition

Branka Radic-Sarikas, Marica Markovic, Caterina Sturtzel, Mathias Ilg, Martha Magdalena Zylka, Didier Surdez, Martin Metzelder, Martin Distel, Aleksandr Ovsianikov, Florian Halbritter, Heinrich Kovar
2025 · doi:10.1101/2025.11.20.689456
preprint OA: gold CC-BY-4.0
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The study developed a standardized three-dimensional (3D) culture and drug-testing platform for Ewing sarcoma and osteosarcoma, using 3D spheroids, bioprinted constructs, and patient-derived xenograft (PDX) cultures to better match in vivo tumor biology than conventional 2D systems. Across these 3D models, the authors found consistent activation and dependency on the mevalonate pathway specifically in Ewing sarcoma. Using this platform, they identified a selective synergy between statins (which inhibit mevalonate pathway flux) and BCL-xL inhibition, a vulnerability that was not detectable in 2D cultures. This paper is centrally about endometriosis and/or adenomyosis; it does not explicitly discuss either condition, and it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Bone sarcomas are rare and aggressive pediatric cancers with limited progress in targeted therapy development, in part 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. 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 that was not detectable in 2D cultures. 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. Our findings show that 3D tumor models can expose actionable metabolic vulnerabilities obscured by traditional approaches, supporting their use in rational combination therapy discovery for aggressive pediatric sarcomas.
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Abstract Bone sarcomas are rare and aggressive pediatric cancers with limited progress in targeted therapy development, in part 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. 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 that was not detectable in 2D cultures. 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. Our findings show that 3D tumor models can expose actionable metabolic vulnerabilities obscured by traditional approaches, supporting their use in rational combination therapy discovery for aggressive pediatric sarcomas. Competing Interest Statement The authors have declared no competing interest.

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[{'doi': '10.13039/501100002428', 'name': 'FWF Austrian Science Fund', 'awards': ['P35353']}, {'doi': None, 'name': None, 'awards': ['7940628']}]

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License: CC-BY-4.0