Targeting protein arginine methyltransferase 5 sensitizes glioblastoma to trametinib

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 glioblastoma. 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 glioblastoma in animal models and is a promising strategy for glioblastoma therapy.

Uncovering the subtype-specific disease module and the development of drug response prediction models for glioma

“…Vinblastine shows sensitivity for both LGG and GBM [ 40 , 41 ] and it is in clinical trials for the treatment of these cancers. Other drugs such as Olaparib [ 42 ], Crizotinib [ 43 ], and Trametinib [ 44 ] have also shown encouraging results for the treatment of brain cancer. Our findings, along with those from the existing literature, suggest that the current approach may be used to aid in clinical decision-making for the treatment of gliomas.…”

Inhibition of epigenetic and cell cycle-related targets in glioblastoma cell lines reveals that onametostat reduces proliferation and viability in both normoxic and hypoxic conditions

“…Importantly, in GB, MTAP is one of the most frequently deleted genes 67 —although it has been shown that the success of PRMT5 inhibition in the context of GB is also dependent on other factors 68 . Still, PRMT5 inhibitors are increasingly studied in the context of both GB cell lines and primary cells 68 , 69 , and some reports also indicate inverse correlation between the PRMT5 expression levels and survival of patients with glioma or GB diagnosis 70 , 71 .…”

5-Fluorouracil dose escalation generated desensitized colorectal cancer cells with reduced expression of protein methyltransferases and no epithelial-to-mesenchymal transition potential

“…For example, for tumors with overexpressed PRMT5, PRMT5 inhibitors can be investigated in combination with common chemotherapeutic agents to overcome chemoresistance. Indeed, the combination of the PRMT5 inhibitor, JNJ-64619178, and trametinib in glioblastoma displayed an increase in the number of apoptotic cells and number of cells in G1 cell cycle arrest than either individual therapy alone [ 56 ]. Thus, health care providers should also consider assessing the expression of PMTs when determining combinational drug regimens for individual cancer patients.…”