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A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcoma
Verónica Rey1, Juan Tornín2, Juan Jose Alba-Linares3
1Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain; CIBER en oncología (CIBERONC), 28029, Madrid, Spain.
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).
Insights
Enasidenib effectively targets mutated IDH2 (mIDH2) chondrosarcomas by reducing the oncometabolite 2-HG and inhibiting tumor growth. This study provides preclinical evidence supporting enasidenib as a potential therapy for mIDH2 chondrosarcomas.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chondrosarcomas are malignant tumors of mesodermal origin.
- High-grade chondrosarcomas are resistant to current therapies.
- Mutations in isocitrate dehydrogenase (IDH) 1 and 2 genes are common in chondrosarcomas and lead to the accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), promoting tumor growth.
Purpose of the Study:
- To investigate the therapeutic potential of targeting mutated IDH (mIDH) in chondrosarcomas.
- To evaluate the efficacy of specific mIDH1/2 inhibitors in preclinical models.
- To explore the molecular mechanisms underlying the anti-tumor effects of effective inhibitors.
Main Methods:
- Personalized medicine strategy using targeted next-generation sequencing (NGS)/Sanger sequencing of sarcoma samples.
- Utilized patient-derived cell lines as a drug-testing platform for in vitro, in vivo, and molecular analyses.
- Analyzed transcriptomic and DNA methylation profiles to understand treatment effects.
Main Results:
- The mIDH2 inhibitor enasidenib reduced 2-HG levels and chondrosarcoma cell viability in vitro.
- Enasidenib administration in xenografted mice led to complete tumor growth abrogation.
- Enasidenib treatment induced significant transcriptomic changes, including repression of proliferative pathways, without altering 5hmC methylation levels.
Conclusions:
- Enasidenib demonstrates significant preclinical efficacy against mIDH2 chondrosarcomas.
- Targeting mIDH2 with enasidenib represents a promising therapeutic strategy for this challenging cancer.
- The study highlights the role of proliferative pathway repression in enasidenib's anti-tumor activity.
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