Metabolic Adaptation as a Driver of Drug Resistance in Chemotolerant Medulloblastoma Cells

Medulloblastoma (MB) is an aggressive central nervous system (CNS) tumour that most commonly affects children under the age of 10. MB patients frequently experience tumour recurrence (20-30%), and despite multimodal therapy—including surgery, chemotherapy, and radiotherapy—the most aggressive forms of MB have extremely poor overall survival rates (40-50%). The rarity of this tumour and the lack of matched samples at both diagnosis and relapse make studying recurrence particularly challenging. In this context, we established an in vitro model of MB resistance to chemotherapy by exposing MB cell lines weekly to a cocktail of chemotherapeutics commonly used in MB treatment (Vincristine, Etoposide, Cisplatin, Cyclophosphamide – VECC). Multi-omics data analysis of these models highlights metabolism as one of the most deregulated hallmarks in MB-resistant cells. We have now demonstrated that chemotherapy significantly reshapes the metabolic landscape of resistant cells. Specifically, we observed modulation in nucleotide metabolism, with a reduction in nucleotide catabolism and increased nucleotide synthesis, as well as a marked increase in fatty acid uptake and utilization. Furthermore, chemotherapy induction triggers an NRF2-dependent accumulation of metabolites such as GSH and NADPH, enhancing redox homeostasis and enabling cells to cope with chemotherapy-induced ROS accumulation. These findings are consistent with the high-throughput drug screening we previously published, which indicated increased sensitivity of resistant cells to antimetabolites. Functional analyses revealed enhanced sensitivity to chemotherapy induction upon NRF2 silencing or inhibition. Additionally, a high NRF2 signature in medulloblastoma patients predicts significantly worse overall survival, indicating the prognostic value of NRF2-related genes. Recent studies emphasize the importance of metabolic plasticity in cancer cells for adapting to chemotherapy. Our data supports the idea that chemotolerant MB cells, through the deregulation of several metabolic pathways, counteract chemotherapy-induced stress by maintaining high antioxidant capacity and macromolecule biosynthesis. Identifying how sensitive cells modulate their metabolism to adapt to chemotherapy resistance has allowed us to uncover a metabolic vulnerability, which can potentially be exploited as an Achilles' heel in MB therapy.