MYC-driven pediatric tumors, such as high-risk neuroblastoma (NB) and group 3 medulloblastoma (G3MB), represent some of the most aggressive and therapy-resistant cancers. To date, only one direct MYC inhibitor has passed a phase I trial, yet its safety and therapeutic potential in pediatric oncology remain unclear. Our findings show that mitochondrial stress-inducing drugs, including common antibiotics, can indirectly suppress MYC proteins and trigger MYC-dependent cell death in multidrug-resistant NB via mitochondrial integrated stress response (mitoISR). This project aims to leverage the identified mitochondrial synthetic lethality as a selective therapeutic approach for tumors dependent on high levels of MYC proteins. Using NB as proof of concept, we will apply our novel cumate-inducible MYC/MYCN models for the first-in-field uncompromised screening for MYC-synthetic lethal drugs in a custom FDA-approved drug library, rationally enriched with ribosomal antibiotics and mitochondrial stressors. Hits will be validated in MYC-driven NB, G3MB, and Burkitt lymphoma cell lines and characterized for mitochondrial selectivity, including luciferase assays in cell-free translation and mitoISR reporter systems. The efficiency of key candidates will be further tested in spheroid cultures and in vivo using a zebrafish model of MYCN-driven NB. To facilitate repurposing for pediatric tumors, potent MYC-synthetic lethal drugs will be prioritized based on known safety profiles, and their therapeutic potential will be assessed in highly relevant preclinical models accessed via multicentric international collaboration: (i) in vitro, in a panel of primary patient-derived cell lines from relapsed/refractory tumors, (ii) in vivo, in zebrafish xenograft and patient-derived xenograft models. This translational research project is designed to deliver robust data that could pave the way for clinical trials of well-tolerated drugs repurposed to treat resistant MYC-driven pediatric tumors.