Purine salvage promotes treatment resistance in H3K27M-mutant diffuse midline glioma

• DOI: 10.1186/s40170-024-00341-7
• Publication Date: 2024-04-09T05:02:01Z
• Authors: Erik R. Peterson; Peter Sajjakulnukit; Andrew J. Scott; Caleb Heaslip; Anthony Andren; Kari Wilder-Romans; Weihua Zhou; Sravya Palavalasa; Navyateja Korimerla; Angelica Lin; Alexandra O’Brien; Ayesha Kothari; Zitong Zhao; Li Zhang; Meredith A. Morgan; Sriram Venneti; Carl Koschmann; Nada Jabado; Costas A. Lyssiotis; Maria G. Castro; Daniel R. Wahl
• Keywords: Hypoxanthine; Purine metabolism

Abstract Background Diffuse midline gliomas (DMG), including diffuse intrinsic pontine (DIPGs), are a fatal form of brain cancer. These tumors often carry driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M characterized by altered metabolism and resistance standard care radiation (RT) but how the H3K27M mediates metabolic response consequent treatment is uncertain. Methods We performed metabolomics irradiated untreated isogenic DMG cell lines observed an H3K27M-specific enrichment for purine synthesis pathways. profiled expression enzymes in publicly available patient data our models, quantified using stable isotope tracing, vitro vivo de novo salvage inhibition combination with RT. Results cells activate fashion. In absence genotoxic treatment, H3K27M-expressing have higher relative activity apparent lower demonstrated via tracing key metabolites hypoxanthine-guanine phosphoribosyltransferase (HGPRT), rate-limiting enzyme into IMP GMP. Inhibition guanylate radiosensitized . Irradiated upregulated HGPRT hypoxanthine-derived maintained high levels guanine-derived salvage. Exogenous guanine supplementation decreased radiosensitization treated RT inhibition. Silencing combined markedly suppressed tumor growth Conclusions Our results indicate that rely highly active synthesis, both from However, free bases mature guanylates can bypass synthetic pathway. conclude inhibiting may be promising strategy overcome tumors.