TMET-20. TARGETING LINKS BETWEEN METHIONINE METABOLISM AND DNA REPAIR TO IMPROVE GBM THERAPY

Abstract

Abstract Glioblastoma (GBM) is uniformly lethal due to intrinsic resistance to standard of care radiation (RT) and chemotherapy. Recent studies have identified altered cellular metabolism as a key mediator of GBM RT resistance. Methionine uptake is drastically elevated in GBMs compared to normal cells but whether this impacts treatment resistance is uncertain, as is the metabolic fates of methionine once it enters GBM cells. Here, we find that RT acutely increases the levels of methionine-related metabolites in a variety of RT-resistant GBM models. Stable isotope tracing studies further revealed that RT acutely activates methionine to S-adenosyl methionine (SAM) conversion through an active signaling event through DNA damage response. We developed in vivo 13C5 methionine stable isotope tracing techniques to confirm these findings in orthotopic models of GBM. Pharmacological and dietary strategies to block methionine to SAM conversion slowed the DNA damage repair and increased cell death following RT. These effects are selective to GBMs lacking the methionine salvage enzyme methylthioadenosine phosphorylase (MTAP). Pharmacologic and dietary strategies to inhibit SAM synthesis hindered tumor growth in flank and orthotopic in vivo GBM models when combined with RT. In short, these results highlight a new signaling link between DNA damage and SAM synthesis and define the metabolic fates of methionine in GBM in vivo. Inhibiting the RT-induced SAM synthesis slows the DNA damage repair and augments RT efficacy in GBM. This therapeutic strategy provides scope for combining MAT2A inhibitors with RT in GBMs with impaired methionine salvage and spares the adjacent normal brain.