ATRT-01. Uncovering Metabolic Diversity and Targetable Vulnerabilities in Atypical Teratoid/Rhabdoid Tumors

Abstract Atypical teratoid/rhabdoid tumours (ATRT) are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF chromatin-remodelling complexes. Despite their aggressive nature, effective therapies for ATRT remain elusive. To uncover genetic vulnerabilities across ATRT subtypes, we conducted genome-scale CRISPR-Cas12 loss-of-function screens in 12 ATRT cell lines. Our study identifies oxidative phosphorylation as a critical metabolic vulnerability. Specifically, complex I genes such as NDUFS1and TIMMDC1 were found to be essential for ATRT cell survival. Building on these findings, we demonstrate that ATRT exhibit significant metabolic diversity, with a subset displaying heightened sensitivity to the complex I inhibitor IACS-010759. Using unbiased metabolomics, we uncovered the pentose phosphate pathway as a key driver of resistance to IACS-010759, rather than differential reliance on anaerobic glycolysis. Furthermore, we identified that sensitivity to IACS-010759 correlates with the differential abundance of glycerol-3-phosphate and dihydroxyacetone phosphate, metabolites involved in the Gro3P-DHAP shuttle. These findings demonstrate the metabolic diversity within ATRT and highlight oxidative phosphorylation as a targetable vulnerability which should be explored as a priority target in the future.