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- W4387579009 abstract "Abstract Background Epidermal growth factor receptor (EGFR) amplification is found in nearly 40%-50% of glioblastoma cases. Several EGFR inhibitors have been tested in glioblastoma but have failed to demonstrate long-term therapeutic benefit, presumably because of acquired resistance. Targeting EGFR downstream signaling with mitogen-activated protein kinase (MEK1/2) inhibitors would be a more effective approach to glioblastoma treatment. We tested the therapeutic potential of MEK1/2 inhibitors in glioblastoma using 3D cultures of glioma stem-like cells (GSCs) and mouse models of glioblastoma. Methods Several MEK inhibitors were screened in an unbiased high-throughput platform using GSCs. Cell death was evaluated using flow cytometry and Western blotting analysis. RNA-seq, real-time quantitative polymerase chain reaction, immunofluorescence, and Western blotting analysis were used to identify and validate neuronal differentiation. Results Unbiased screening of multiple MEK inhibitors in GSCs showed anti-proliferative and apoptotic cell death in sensitive cell lines. An RNA-seq analysis of cells treated with trametinib, a potent MEK inhibitor, revealed upregulation of neurogenesis and neuronal differentiation genes, such as achaete-scute homolog 1 (ASCL1), delta-like 3 (DLL3), and neurogenic differentiation 4 (NeuroD4). We validated the neuronal differentiation phenotypes in vitro and in vivo using selected differentiation markers (β-III-tubulin, ASCL1, DLL3, and NeuroD4). Oral treatment with trametinib in an orthotopic GSC xenograft model significantly improved animal survival, with 25%-30% of mice being long-term survivors. Conclusions Our findings demonstrated that MEK1/2 inhibition promotes neuronal differentiation in glioblastoma, a potential additional mechanism of action of MEK1/2 inhibitors. Thus, MEK inhibitors could be efficacious in glioblastoma patients with activated EGFR/MAPK signaling." @default.
- W4387579009 created "2023-10-13" @default.
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- W4387579009 date "2023-10-12" @default.
- W4387579009 modified "2023-10-14" @default.
- W4387579009 title "Neuronal differentiation drives the anti-tumor activity of MEK inhibition in glioblastoma" @default.
- W4387579009 doi "https://doi.org/10.1093/noajnl/vdad132" @default.
- W4387579009 hasPublicationYear "2023" @default.
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