Advanced soft-tissue sarcomas have few options beyond doxorubicin, which helps only a minority — so new targets matter. This preclinical study makes the first case for PRMT5, an arginine methyltransferase already pursued in epithelial cancers, in sarcoma. High PRMT5 expression tracked with worse metastasis-free survival across two large patient datasets, and the selective inhibitor GSK3326595 curbed proliferation and clonogenicity in seven sarcoma cell lines and slowed growth in two liposarcoma mouse models. Transcriptomic and metabolic profiling — analyzed by Explicyte — pinned the mechanism to glycolysis: PRMT5 blockade downregulated key glycolytic enzymes and cut glucose uptake and lactate output, positioning PRMT5 as a metabolic target worth clinical study in sarcoma.
This preclinical study in Cancer Research Communications, first-authored by Dr. Stéphanie Verbeke and led by Prof. Antoine Italiano at the Bergonié Institute Sarcoma Unit and INSERM U1312 BRIC (University of Bordeaux), provides the first evidence that PRMT5 is a therapeutic target in soft-tissue sarcoma. The team paired patient prognostic data with pharmacologic inhibition of PRMT5 using GSK3326595 (GSK595, supplied by GlaxoSmithKline) across cell lines and xenograft models, then dissected the mechanism through transcriptomics and metabolic profiling. The work was funded by the SIRIC BRIO integrated cancer research site (IMS program). Explicyte generated the NanoString nCounter metabolic-pathway data and carried out the bioinformatic analysis of both the RNA-seq and NanoString datasets — the work that identified glycolysis as the pathway PRMT5 inhibition shuts down.
Mining TCGA/GTEx (via GEPIA) plus two French Sarcoma Group cohorts — 255 translocation-related and 389 complex-genomic sarcomas — the team found PRMT5 overexpressed in tumor versus normal tissue and significantly associated with worse survival. High PRMT5 tracked with shorter metastasis-free survival in both the translocation-related (P = 0.003) and complex-genomic (P = 0.009) datasets, establishing prognostic rationale for targeting it.
The selective inhibitor GSK595 suppressed viability across all seven sarcoma cell lines (IC50 0.01–1.4 µmol/L) spanning leiomyosarcoma, dedifferentiated liposarcoma, UPS, myxofibrosarcoma, and extraskeletal osteosarcoma, lowering the PRMT5 activity marker SDMA and raising p53/p21. Effect was largely independent of TP53 status. Rather than killing cells (apoptosis was minimal), GSK595 sharply cut proliferation and clonogenicity, and in two liposarcoma NSG-xenograft models (IB111, IB115) it slowed tumor growth and extended survival without weight-loss toxicity.
To find the mechanism, Explicyte analyzed RNA-seq of treated IB111 cells — 1,042 differentially expressed genes, with pathway enrichment pointing squarely at downregulated glycolysis. Extending to four cell lines, Explicyte generated and analyzed a NanoString nCounter Metabolic Pathways panel dataset, finding 82 differentially expressed metabolic genes and confirming coordinated downregulation of glycolysis, cell-cycle, and fatty-acid-synthesis programs.
Western blotting across the cell-line panel showed PRMT5 inhibition lowered the glycolytic enzymes PFKL, LDHD, and PCK2, raised the glycolysis-restraining TIGAR, and cut proliferation-marker phospho-Rb. Functionally, GSK595-treated cells showed markedly reduced glucose uptake and lactate production — direct confirmation that blocking PRMT5 throttles aerobic glycolysis in sarcoma cells.
The study converts PRMT5 from an epithelial-cancer target into a credible sarcoma target with a clear, metabolism-based mechanism of action
For sarcoma drug developers, this is an early but coherent target-validation package: prognostic association, pharmacologic efficacy in vitro and in vivo, and a mechanism (glycolytic shutdown) that is not tumor-type specific. PRMT5 inhibitors including GSK3326595 are already in phase 1 solid-tumor studies where sarcoma patients have been scarce, and this work argues for deliberately including sarcoma subtypes in future trials. The metabolic mechanism also suggests glycolysis-related pharmacodynamic readouts — glucose uptake, lactate, key enzyme expression — as candidate markers of PRMT5 target engagement. The authors note the in vivo work used a limited set of models, so generalization across sarcoma subtypes needs further study.
