Résumé
Introduction: Soft tissue sarcomas (STS) are a heterogeneous group of rare tumors representing 1% of solid tumors in adults and 15% in children. Despite adequate locoregional treatment, up to 40% of patients will develop metastatic disease. Doxorubicin represents the 1st line standard of care for patients in this setting. However, its activity is limited with a response rate of only 10%, a progression-free survival of less than 6-months. New therapeutic strategies are therefore urgently needed. PRMT5 belongs to a family of enzymes that catalyze the methylation of arginine residues on both histones and non-histone proteins. Recent evidence shows that PRMT5 is upregulated in a wide variety of cancers. Its expression and activity are associated with tumorigenesis and with a decrease in patient survival in several cancers, a rationale for developing highly potent inhibitors. Methods: We analyzed the transcriptome data from 255 translocation-related STS and 389 complex genomics STS with annotated clinical data from the French Sarcoma Group. We then investigated the anti-tumor activity of the first -in class PRMT5 specific inhibitor, GSK3226593 in a panel of 7 cell lines and in two xenograft models established at Institut Bergonié (Bordeaux, France). Results: We found that high PRMT5 gene expression level was significantly associated with worse metastases-free survival in both translocation-related and complex genomics STS (p=0.003 and p=0.009, respectively), support the relevance of PRMT5 as a potential therapeutic target in this indication. We then found that pharmacological inhibition of PRMT5 by using GSK3226593, suppressed the viability and the cell proliferation of 7 STS cell lines in vitro (IC50 range between 0.01 and 1.4 µM) as well as in vivo in two models of xenograft cell lines. This inhibition of cell growth was concomitant with an increase of p53 and p21 expression. However, anti-tumor activity of GSK3226593 was independent of p53 since the compound was still active in shp53 expressing cell lines. Moreover, we did not notice any significant effect of GSK3226593 on cell cycle phases or apoptosis. To decipher the mechanism of action of PRMT5 inhibition in STS, we did a comparative transcriptomic analysis (RNAseq) of STS cells before and after 10 days of treatment with GSK3226593. Gene Ontology and gene set enrichment analysis revealed downregulation of metabolic processes especially glycolysis and mTORC1 pathways. A specific metabolic pathway panel was used to confirm and deepen the underlying molecular mechanism. The downregulation of several genes by GSK3226593 such as PCK2 was confirmed at the protein level by Western blot. Glycolysis inhibition was confirmed by a decrease of glucose uptake. Conclusion: PRMT5 inhibition has anti-tumor activity in vitro and in vivo through the regulation of STS cell metabolism providing a clear rationale for its clinical investigation in this indication. Citation Format: Stephanie Verbeke, Laura Leroy, Aurelien Bourdon, Vanessa Chaire, Elodie Richard, Jean-Philippe Guegan, Alban Bessede, Antoine Italiano. PRMT5 inhibition suppress soft tissue sarcomas tumorigenicity through the regulation of glucose metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3937.