Molecular Profiling of Belumosudil-Treated IOMM-Lee Meningioma Cells Reveals Repurposing Potential via Enhanced Oxidative Phosphorylation and ROS-Mediated Cell Death

Abstract

Meningioma is the most prevalent primary brain tumor. The aggressive forms of the tumor pose a major challenge to clinicians, as it becomes difficult to eradicate them surgically. This has necessitated a concerted effort to explore novel therapeutic candidates. A multiomics-based pathway analysis, followed by drug repurposing, was undertaken to identify a suitable drug candidate that could potentially be used to control proliferation. Multiomics analysis indicates that IOMM-Lee (high-grade meningioma) cells show enhanced oxidative phosphorylation and ROS-mediated cell-death upon treatment with belumosudil, an FDA-approved Rho kinase inhibitor. Dysregulation of key pathways, including Wnt, p53, and phosphoinositol signaling, was also observed. It suggests that the drug treatment induces a ROS-rich environment, primarily affecting the nucleus and mitochondria. The cellular metabolome also shows an increase in lipid peroxidation product in concordance to an increase in ROS production. The intracellular and mitochondrial ROS concentrations have also been found to be increased with FACS-based assays. The efficacy of belumosudil observed in the cell-line-based study opens up the possibility of advancing to the next stages of in vivo studies and clinical trials for its use in the treatment of high-grade meningioma, either as a standalone therapy or in combination with other therapeutics.