Targeting protein arginine methyltransferase 5 sensitizes glioblastoma to trametinib

• Published in: Neuro-oncology advances Vol. 4; no. 1; p. vdac095
• Main Authors: Banasavadi-Siddegowda, Yeshavanth Kumar, Namagiri, Sriya, Otani, Yoshihiro, Sur, Hannah, Rivas, Sarah, Bryant, Jean-Paul, Shellbourn, Allison, Rock, Mitchell, Chowdhury, Ashis, Lewis, Cole T, Shimizu, Toshihiko, Walbridge, Stuart, Kumarasamy, Sivarajan, Shah, Ashish H, Lee, Tae Jin, Maric, Dragan, Yan, Yuanqing, Yoo, Ji Young, Kumbar, Sangamesh G, Heiss, John D, Kaur, Balveen
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.01.2022
• Subjects: Basic and Translational Investigations; trametinib; PRMT5; AKT; glioblastoma; ERBB3
• ISSN: 2632-2498; 2632-2498
• DOI: 10.1093/noajnl/vdac095

Abstract 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.