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Article Dans Une Revue EBioMedicine Année : 2024

A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcoma

Cristina Robledo
  • Fonction : Auteur
Karoly Szuhai

Résumé

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.
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Origine : Publication financée par une institution
Licence : CC BY - Paternité

Dates et versions

inserm-04524777 , version 1 (28-03-2024)

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Verónica Rey, Juan Tornín, Juan Jose Alba-Linares, Cristina Robledo, Dzohara Murillo, et al.. A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcoma. EBioMedicine, 2024, 102, pp.105090. ⟨10.1016/j.ebiom.2024.105090⟩. ⟨inserm-04524777⟩
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