MAGMAS Inhibition Enhances Temozolomide Efficacy in Chemotherapy-Resistant Glioblastoma Models

Abstract Glioblastoma (GBM, isocitrate dehydrogenase wildtype grade 4 astrocytoma) is the most aggressive and common brain tumor, characterized by increased proliferation, invasiveness, mitochondrial-dependent changes, and necrosis. GBM recurrence is universal despite the standard of care treatment with maximal surgical resection, radiation, and temozolomide (TMZ). Most patients relapse 6 to 9 months following initial diagnosis, and median survival after recurrence is less than a year. Therefore, effective therapeutic strategies are needed to overcome glioma resistance mechanisms and improve long-term outcomes for GBM patients. Mitochondria-associated granulocyte macrophage colony-stimulating factor molecule (MAGMAS, PAM16) is a nuclear-encoded mitochondrial protein subunit of the translocase of the inner membrane 23 (TIM23) complex that functions as an essential regulator of protein trafficking into the mitochondrial matrix. We previously demonstrated that MAGMAS is overexpressed in GBM, and that the small molecule MAGMAS inhibitor BT9 reduces mitochondrial respiration and is cytotoxic to glioma cells in vitro. Here, we investigated the role of MAGMAS in GBM biology and the effects of MAGMAS inhibition on TMZ-resistant glioma lines and patient-derived glioma stem-like cells (GSCs). We observed elevated PAM16 levels in recurrent GBM, chemoresistant glioma cells, and during metabolic switching processes. Concurrent treatment with BT9 and TMZ significantly increased cell death compared to either drug alone in all glioma lines, irrespective of their TMZ resistance status. Additionally, GBM cells constitutively expressing shPAM16 became sensitized to TMZ both in vitro and in vivo in an intracranial xenograft model. Our findings suggest that targeting MAGMAS holds promise as a novel, effective therapeutic strategy for GBM.