Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2023.09.12.557334

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

Rey, V.·Tornin, J.·Alba-Linares, J. J.·Robledo, C.·Murillo, D.·Rodriguez, A.·Gallego, B.·Huergo, C.·Brana, A.·Astudillo, A.·Heymann, D.·Fernandez, A. F.·Fraga, M. F.·Alonso, J.·Rodriguez, R.
View original source ↗Export metadata ↓

Abstract

BackgroundSarcomas represent an extensive group of malignant diseases affecting mesodermal tissues. Among sarcomas, the clinical management of chondrosarcomas remains a complex challenge, as high-grade tumors 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 tumor growth. MethodsWe 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-tumor potential of IDH mutations found in two chondrosarcoma cases was analyzed in vitro, in vivo and molecularly (transcriptomic and DNA methylation analyses). FindingsWe 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 tumor growth. Enasidenib induced a profound remodeling of the transcriptomic landscape not associated to changes in the 5mC methylation levels and its anti-tumor effects were associated with the repression of proliferative pathways such as those controlled by E2F factors. InterpretationOverall, this work provides the first preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas. FundingSpanish Research Agency (grants PID2019-106666RB-I00; PI20CIII/00020; DTS18CIII/00005; CB16/12/00390; CB06/07/1009; CB19/07/00057). RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSSarcomas represent an extensive group of malignant diseases affecting mesodermal tissues. The genomic nature of most sarcoma subtypes, displaying high inter- and intra-tumor heterogeneity with few recurrent driver mutations in a small portion of patients, makes these tumors especially indicated for personalized treatment approaches. For optimal development of these personalized protocols and a more efficient translation to the clinic, it is necessary to create patient-derived models suitable for testing the efficiency of candidate therapies. These strategies might be especially indicated for chondrosarcomas, a subtype of bone sarcoma that is inherently resistant to current therapies. Added value of this studyTo develop a personalized medicine strategy for sarcomas we have applied targeted sequencing protocols to detect druggable mutations in a collection of sarcomas cases with available patient-derived models. Among those potential druggable alterations detected in patient samples and avatar cell lines, we found IDH mutations in two chondrosarcomas. The presence of mutated IDH enzymes results in the accumulation of the oncometabolite 2-HG which contributes to driving tumor growth. In vitro and in vivo experiments evidenced the anti-tumor potential of the IDH mutant inhibitor enasidenib for the treatment of IDH2 mutant chondrosarcomas. Our transcriptomic and epigenomic analyses show that the mechanism of action of this drug is associated with the repression of proliferative pathways rather than with the promotion of tumor differentiation. Implications of all the available evidenceThis study suggests that enasidenib may represent an efficient therapeutic alternative for mutant IDH2 chondrosarcomas. This anti-proliferative mechanism of action of this drug may be especially relevant in dedifferentiated chondrosarcomas where reversal of this phenotype is not possible. In addition, this work provides support for the use of sarcoma patient-derived lines as avatar models capable of predicting (pre)-clinical responses in personalized medicine strategies.

Source connections

Explore related subjects

cancer biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Rey, V., Tornin, J., Alba-Linares, J. J., Robledo, C., Murillo, D., Rodriguez, A., Gallego, B., Huergo, C., Brana, A., Astudillo, A., Heymann, D., Fernandez, A. F., Fraga, M. F., Alonso, J., Rodriguez, R.. 2023-09-12. A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcoma. https://doi.org/10.1101/2023.09.12.557334

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

The Phospholipase A2 Activity of Peroxiredoxin 6 Protects Hepatocarcinoma Cells Against Ferroptosis and Mitophagy Impairment

Peroxiredoxin 6 (PRDX6) is a moonlighting protein that plays a key role in regulating redox homeostasis and lipid metabolism through its unique dual peroxidase and calcium-independent phospholipase A2 (iPLA2) activities. Here, we generated a stable HepG2 cell line harboring a D140A mutation to selectively ablate iPLA2 activity, and we compared its phenotype with that of wild-type (WT) and PRDX6-knockout (KO) cells. D140A exhibited low ROS leves, similar to WT cells, confirming that oxidative stress is due to peroxidase deficiency. In contrast, D140A cells displayed higher lipid peroxidation than WT cells, though significantly lower than that of KO cells. Furthermore, the D140A mutant mirrored the KO phenotype regarding intracellular ferrous iron accumulation, impaired lipid droplet biogenesis, and the downregulation of the key ferroptosis regulator GPX4. Mechanistically, integrated proteomic, lipidomic, and enzymatic analyses revealed that a deficiency in iPLA2 activity of PRDX6 disrupted the release of key lipid species necessary for cell structure and signaling. Consequently, organelles involved in lipid synthesis and trafficking, such as peroxisomes, endoplasmic reticulum, mitochondria and lipid droplet, were affected. Specifically, we found that mitochondria exhibited a reduction in cristae and a diminished capacity for mitophagy and autophagy, which ultimately makes cells much more susceptible to erastin-induced ferroptotic cell death. Taken together, our findings demonstrate that PRDX6 iPLA2 activity uniquely coordinates organelle lipid homeostasis and mitophagy to protect cancer cells from ferroptotic cell death. Consequently, the use of iPLA2 inhibitors such as MJ33, which decreased PRDX6 iPLA2 activity to a level comparable to the mutant D140A, could represent a promising therapeutic strategy for inducing ferroptotic cell death in hepatocellular carcinoma.

cancer biology↗
bioRxiv2026

Serum extracellular vesicle proteomics reveals treatment-associated biomarkers in pancreatic ductal adenocarcinoma

Background Longitudinal biomarkers of treatment response in pancreatic ductal adenocarcinoma (PDAC) are needed. Extracellular vesicle (EV)-enriched serum proteomics may provide a minimally invasive approach for monitoring systemic and tumor-associated responses to therapy. Methods Paired pre-treatment and post-treatment serum samples were analyzed from 51 patients with pancreatic cancer, including 25 treated with FOLFIRINOX and 20 treated with gemcitabine-based therapy. EVs were enriched using the Mag-Net method and profiled by data independent acquisition mass spectrometry. After batch correction and filtering, 941 proteins were retained for differential and pathway analyses. Paired linear models and gene set enrichment analyses were used to assess treatment-associated changes. Baseline protein abundance and longitudinal changes were evaluated in relation to overall survival (OS) using Cox models. Results A total of 2,089 EV-associated proteins were identified, with an average of 1,186 proteins quantified per sample. Across the cohort, 26 proteins differed between post- and pretreatment samples. Proteins that increased after treatment were primarily related to extracellular matrix organization and cell adhesion, whereas proteins that decreased after treatment were associated with actin cytoskeletal organization, coagulation, and hemostasis. Treatment-associated changes were more pronounced in the FOLFIRINOX group, in which 32 proteins were differentially expressed. FOLFIRINOX was characterized by coordinated reductions in platelet- and coagulation-associated proteins, including PF4, PF4V1, PPBP, GP5, ITGA2B, and ITGB3, accompanied by enrichment of platelet activation, coagulation, and hemostasis pathways among down-regulated processes. No individual proteins met the same significance threshold in the gemcitabine group. A composite seven-protein platelet score decreased significantly after FOLFIRINOX but not for gemcitabine, and the between-regimen difference in score change was significant. Higher pretreatment ITGB1 abundance was associated with longer OS after multiple-testing correction (HR, 0.112; BH-FDR = 0.0063). In multivariable analysis, greater treatment-associated platelet-score depletion was independently associated with shorter OS (HR per unit increase in {Delta}score, 0.56; P = 0.030). Conclusions Longitudinal serum EV-enriched proteomics identified treatment-associated biological changes in PDAC, including a coordinated platelet-related response predominantly observed after FOLFIRINOX. Baseline ITGB1 abundance and longitudinal platelet-score changes represent potentially complementary prognostic and pharmacodynamic markers. These findings are exploratory and require validation in larger, independent cohorts incorporating platelet counts, coagulation measurements, and targeted proteomic assays.

cancer biology↗
bioRxiv2026

BAF complexes cooperate with lineage-restricted transcription factors to establish cell-state-specific regulatory programs

BRG1/BRM-associated factor (BAF) complexes are essential regulators of chromatin organization and cell identity. Genes encoding BAF subunits are among the most frequently mutated in human cancer. Yet, how disruption of a single subunit gives rise to distinct tumor states remains poorly understood. Atypical teratoid rhabdoid tumors (ATRTs) provide a compelling model, as they are uniformly driven by bi-allelic loss of the BAF subunit SMARCB1, yet segregate into distinct molecular subtypes. Using integrated multi-omics profiling of patient-derived ATRT organoids and primary tumor tissues, we show that transcriptional and chromatin accessibility changes upon SMARCB1 reconstitution are directed by subtype- and lineage-specific transcription factor (TF) repertoires. Genome-wide binding and transcriptomic analyses reveal that SMARCB1 reconstitution enables the lineage-specific TF RFX4 to engage regulatory elements and activate neuronal differentiation programs, partially reprogramming ATRT-MYC toward an ATRT-SHH-like identity. Together, these findings demonstrate that SMARCB1 loss disrupts TF-dependent chromatin priming, revealing that the lineage-specific regulatory output of BAF complexes is constrained by the underlying TF repertoire.

cancer biology↗