What question did this study set out to answer?

This research aims to evaluate the combined effects of arsenic trioxide and the MNK1 inhibitor AUM001 on glioblastoma cells.

January 25, 2026Open Access

Arsenic Trioxide and the MNK1 Inhibitor AUM001 Exert Synergistic Anti-Glioblastoma Effects by Modulating Key Translational, Cell Cycle, and Transmembrane Transport Pathways

Key Points

This research aims to evaluate the combined effects of arsenic trioxide and the MNK1 inhibitor AUM001 on glioblastoma cells.
Assessed therapeutic effects of ATO alone and with AUM001 in patient-derived xenograft models.
Investigated the molecular determinants of sensitivity and synergy in glioblastoma models.
Conducted transcriptomic analyses to identify pathways associated with treatment response.
Resistance to ATO is more pronounced in certain GBM subtypes but shows synergistic effects with AUM001.
Combination therapy significantly reduces glioblastoma stem cell frequency compared to single treatments.
Distinct molecular signatures influence the effectiveness of the combination therapy across GBM subtypes.

Abstract

Background: The profound heterogeneity of glioblastoma and the often-limited efficacy of conventional treatments, including arsenic trioxide (ATO), underscore the urgent and critical demand for innovative combination strategies specifically designed to overcome treatment resistance. Methods: We evaluated the therapeutic effects of ATO as a single agent and in combination with the MNK1 inhibitor AUM001 across patient-derived xenograft (PDX) models and investigated molecular determinants of sensitivity and synergy. Our results demonstrated that GBM models resistant to ATO, particularly those of the mesenchymal subtype, are more likely to show synergistic cytotoxicity when AUM001 is added. The combination significantly reduces the frequency of glioblastoma stem cells (GSCs) compared to either drug alone, especially in ATO-resistant models. Results: These observations suggest that targeting the MNK1 pathway in conjunction with ATO is a promising strategy to specifically eradicate GSCs, which are major drivers of GBM recurrence and therapeutic failure. Transcriptomic analyses revealed that ATO sensitivity correlated with activated translation-related pathways and cell cycle processes, while synergistic responses to the combination were driven by distinct molecular signatures in different GBM subtypes. Overall, synergistic response to the combination therapy is more associated with cellular organization, amino acid transmembrane transporter activity, ion channels, extracellular matrix organization and collagen formation. Conclusions: Our findings highlight that specific molecular pathways and their activities, including those involving translation, cell cycle and ion transport, appear to modulate the synergistic efficacy of the ATO and AUM001 combination, thereby offering potential biomarkers for improved patient stratification in future GBM clinical trials of such ATO-based treatments.

Arsenic Trioxide and the MNK1 Inhibitor AUM001 Exert Synergistic Anti-Glioblastoma Effects by Modulating Key Translational, Cell Cycle, and Transmembrane Transport Pathways

Key Points

Abstract

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