Academic Journal
A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcomaResearch in context
| Title: | A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcomaResearch in context |
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| Authors: | Verónica Rey, Juan Tornín, Juan Jose Alba-Linares, Cristina Robledo, Dzohara Murillo, Aida Rodríguez, Borja Gallego, Carmen Huergo, Cristina Viera, Alejandro Braña, Aurora Astudillo, Dominique Heymann, Karoly Szuhai, Judith V.M.G. Bovée, Agustín F. Fernández, Mario F. Fraga, Javier Alonso, René Rodríguez |
| Source: | EBioMedicine, Vol 102, Iss , Pp 105090- (2024) |
| Publisher Information: | Elsevier, 2024. |
| Publication Year: | 2024 |
| Collection: | LCC:Medicine LCC:Medicine (General) |
| Subject Terms: | Chondrosarcoma, Enasidenib, IDH2, Patient-derived models, Personalized medicine, Medicine, Medicine (General), R5-920 |
| More Details: | Summary: 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. Funding: Supported by the Spanish Research Agency/FEDER (grants PID2022-142020OB-I00; PID2019-106666RB-I00), the ISC III/FEDER (PI20CIII/00020; DTS18CIII/00005; CB16/12/00390; CB06/07/1009; CB19/07/00057); the GEIS group (GEIS-62); and the PCTI (Asturias)/FEDER (IDI/2021/000027). |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2352-3964 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S2352396424001257; https://doaj.org/toc/2352-3964 |
| DOI: | 10.1016/j.ebiom.2024.105090 |
| Access URL: | https://doaj.org/article/a9bcedfaab4940eeb62fdf6d5e65245e |
| Accession Number: | edsdoj.9bcedfaab4940eeb62fdf6d5e65245e |
| Database: | Directory of Open Access Journals |
| ISSN: | 23523964 |
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| DOI: | 10.1016/j.ebiom.2024.105090 |
| Published in: | EBioMedicine |
| Language: | English |