Inhibition of mitochondrial protein MAGMAS increases sensitivity to standard of care treatment

Glioblastoma is a highly aggressive CNS cancer that affects 3 in 100,000 people every year in the U.S. The majority of patients experience tumor recurrence within the first year after initial diagnosis and after receiving standard of care treatment. GBM is characterized by its high mitotic index, capacity to invade other regions of the brain and modulate the tumor microenvironment (TME). Options are extremely limited for patients suffering from recurrent GBM as tumors become increasingly resistant to chemotherapy. Resistance to chemotherapy can be attributed to several factors that include DNA damage response (DDR), glioma stem cells (GSCs), TME, senescence mechanisms, and metabolic reprogramming. Mitochondria-associated granulocyte macrophage colony-stimulating factor molecule (MAGMAS), a mitochondria protein and subunit of the translocase of the inner membrane 23 (TIM23) complex, regulates protein trafficking into the mitochondria by recruiting DNAJC19 to the TIM23 complex. The present work was to investigate the role of MAGMAS in GBM tumor biology and mechanisms of resistance to TMZ. Computational analysis of MAGMAS/PAM16 expression levels from publicly available databases revealed that MAGMAS levels are significantly elevated in recurrent tumors and is positively correlated with the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) expression in primary patient tissues. We generated genetically modified glioma cells expressing shpam16 constructs and found that MAGMAS deficient glioma cells were sensitized to standard of care treatment that include TMZ, radiation and tumor treating fields (TTFs). Additionally, we discovered that silencing PAM16/MAGMAS reduced MGMT expression and reduced extracellular excretion of lactic acid. Interestingly, we also discovered that the cytokine IL7 and IL15 were significantly upregulated in MAGMAS KD cells. Taken together, our results demonstrate that MAGMAS plays an important role in chemotherapy resistance, metabolic reprogramming and potentially modulating the TME. By targeting MAGMAS, we can promote favorable conditions to enhance anti-tumor response using immunotherapy strategies in the future.