2026-04-29T03:31:36Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/193032025-05-09T09:34:01Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19616

00925njm 22002777a 4500 dc Rey, Verónica author Tornin, Juan author Alba-Linares, Juan José author Robledo, Cristina author Murillo, Dzohara author Rodríguez, Aida author Gallego, Borja author Huergo, Carmen author Viera, Cristina author Braña, Alejandro author Astudillo, Aurora author Heymann, Dominique author Szuhai, Karoly author Bovée, Judith V M G author Fernandez, Agustín F author Fraga, Mario F author Alonso, Javier author Rodriguez, Rene author 2024-04 Background: Sarcomas represent an extensive group of malignant diseases affecting mesodermal tissues. Among sarcomas, the clinical management of chondrosarcomas remains a complex challenge, as high-grade tumours do not respond to current therapies. Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes are among the most common mutations detected in chondrosarcomas and may represent a therapeutic opportunity. The presence of mutated IDH (mIDH) enzymes results in the accumulation of the oncometabolite 2-HG leading to molecular alterations that contribute to drive tumour growth. Methods: We developed a personalized medicine strategy based on the targeted NGS/Sanger sequencing of sarcoma samples (n = 6) and the use of matched patient-derived cell lines as a drug-testing platform. The anti-tumour potential of IDH mutations found in two chondrosarcoma cases was analysed in vitro, in vivo and molecularly (transcriptomic and DNA methylation analyses). Findings: We treated several chondrosarcoma models with specific mIDH1/2 inhibitors. Among these treatments, only the mIDH2 inhibitor enasidenib was able to decrease 2-HG levels and efficiently reduce the viability of mIDH2 chondrosarcoma cells. Importantly, oral administration of enasidenib in xenografted mice resulted in a complete abrogation of tumour growth. Enasidenib induced a profound remodelling of the transcriptomic landscape not associated to changes in the 5 mC methylation levels and its anti-tumour effects were associated with the repression of proliferative pathways such as those controlled by E2F factors. Interpretation: Overall, this work provides preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas. EBioMedicine. 2024 Apr:102:105090. 2352-3964 http://hdl.handle.net/20.500.12105/19303 38547578 10.1016/j.ebiom.2024.105090 2352-3964 EBioMedicine Chondrosarcoma Enasidenib IDH2 Patient-derived models Personalized medicine A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcoma