Abstract 1095: Exploiting altered methionine metabolism to overcome treatment resistance in glioblastoma

Abstract

Abstract Glioblastoma (GBM) is the most aggressive adult brain tumor and is uniformly fatal due to resistance to standard therapies such as radiation (RT) and chemotherapy. Our group and others have identified altered metabolism as a key mediator of GBM RT resistance. Methionine is an essential sulfur-containing amino acid that cells use to synthesize antioxidants, polyamines and S-adenosyl methionine (SAM), which drives intracellular methylation reactions. Methionine uptake is dramatically elevated in GBM compared to normal brain, but what GBMs use this methionine for, and whether it governs GBM treatment resistance, is unknown. Here, we find that RT acutely increases the levels of numerous methionine-related metabolites in multiple RT-resistant GBM models. To interrogate metabolic pathway activity, we used 13C5 methionine stable isotope tracing to show that GBMs respond to RT by activating the conversion of methionine to SAM, which is dependent on signaling through the DNA damage response. We developed in vivo methionine stable isotope tracing techniques to confirm these findings in orthotopic PDX models of GBM. Blocking the conversion of methionine to SAM, through pharmacologic inhibition of methionine adenosyltransferase 2A (MAT2A), slowed the repair of RT-induced DNA damage and increased cell death in GBM models following RT. These effects were especially pronounced in GBM models lacking the methionine salvage enzyme methylthioadenosine phosphorylase (MTAP). Pharmacologic inhibition of MAT2A in flank and orthotopic in vivo GBM models depleted SAM levels and slowed tumor growth when combined with RT. Combining MAT2A inhibition with dietary methionine restriction and RT slowed GBM tumor growth even further. Together, our work demonstrates a new signaling link between DNA damage and methionine-driven SAM synthesis in GBM. Inhibiting SAM synthesis slows the repair of RT-induced DNA damage and augments RT efficacy. This therapeutic strategy may be especially effective in GBMs defective in methionine salvage and spare normal cortex in which methionine salvage is active. Citation Format: Navyateja Korimerla, Kari-Wilder Romans, Peter Kalev, Ayesha Kothari, Nathan Qi, Charles Evans, Maureen Kachman, Marc L Hyer, Katya Marjon, Taryn Sleger, Daniel R Wahl. Exploiting altered methionine metabolism to overcome treatment resistance in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1095.