Targeting protein arginine methyltransferase 5 sensitizes glioblastoma to trametinib.

Autor:	Banasavadi-Siddegowda YK; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA., Namagiri S; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA., Otani Y; Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, Texas, USA., Sur H; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA., Rivas S; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA., Bryant JP; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA., Shellbourn A; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA., Rock M; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA., Chowdhury A; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA., Lewis CT; Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, Texas, USA., Shimizu T; Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, Texas, USA., Walbridge S; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA., Kumarasamy S; Department of Biomedical Sciences Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA., Shah AH; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA., Lee TJ; Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, Texas, USA., Maric D; Flow and Imaging Cytometry Core Facility, NINDS, NIH, Bethesda, Maryland, USA., Yan Y; Department of Surgery, Northwestern University, Chicago, Illinois, USA., Yoo JY; Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, Texas, USA., Kumbar SG; Department of Orthopedic Surgery, University of Connecticut Health, Farmington, Connecticut, USA., Heiss JD; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA., Kaur B; Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, Texas, USA.
Jazyk:	angličtina
Zdroj:	Neuro-oncology advances [Neurooncol Adv] 2022 Jun 20; Vol. 4 (1), pp. vdac095. Date of Electronic Publication: 2022 Jun 20 (Print Publication: 2022).
DOI:	10.1093/noajnl/vdac095
Abstrakt:	Background: The prognosis of glioblastoma (GBM) remains dismal because therapeutic approaches have limited effectiveness. A new targeted treatment using MEK inhibitors, including trametinib, has been proposed to improve GBM therapy. Trametinib had a promising preclinical effect against several cancers, but its adaptive treatment resistance precluded its clinical translation in GBM. Previously, we have demonstrated that protein arginine methyltransferase 5 (PRMT5) is upregulated in GBM and its inhibition promotes apoptosis and senescence in differentiated and stem-like tumor cells, respectively. We tested whether inhibition of PRMT5 can enhance the efficacy of trametinib against GBM. Methods: Patient-derived primary GBM neurospheres (GBMNS) with transient PRMT5 knockdown were treated with trametinib and cell viability, proliferation, cell cycle progression, ELISA, and western blot were analyzed. In vivo, NSG mice were intracranially implanted with PRMT5-intact and -depleted GBMNS, treated with trametinib by daily oral gavage, and observed for tumor progression and mice survival rate. Results: PRMT5 depletion enhanced trametinib-induced cytotoxicity in GBMNS. PRMT5 knockdown significantly decreased trametinib-induced AKT and ERBB3 escape pathways. However, ERBB3 inhibition alone failed to block trametinib-induced AKT activity suggesting that the enhanced antitumor effect imparted by PRMT5 knockdown in trametinib-treated GBMNS resulted from AKT inhibition and not ERBB3 inhibition. In orthotopic murine xenograft models, PRMT5-depletion extended the survival of tumor-bearing mice, and combination with trametinib further increased survival. Conclusion: Combined PRMT5/MEK inhibition synergistically inhibited GBM in animal models and is a promising strategy for GBM therapy. (Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology 2022.)
Databáze:	MEDLINE
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