TMET-65. SETD2 Loss Predicts Favorable Prognosis in Glioblastoma via Suppression of the Serine Synthesis Pathway

BACKGROUND Glioblastoma (GBM) is an aggressive primary brain tumor characterized by poor prognosis and limited treatment options. SETD2, a histone H3K36 trimethyltransferase, maintains genomic integrity and regulates transcriptional and metabolic processes. Although SETD2 loss has been associated with altered metabolism and oxidative stress, its prognostic and mechanistic implications in GBM remain unclear. METHODS We analyzed clinical and transcriptomic datasets to evaluate the association between SETD2 mutations and expression levels and GBM patient outcomes. To investigate the underlying mechanisms, we employed both SETD2 knockdown (KD) and pharmacological inhibition using EZM0414 in U87MG GBM cells. We assessed changes in cell proliferation, survival, and radiosensitivity following SETD2 suppression. RNA sequencing was performed to investigate the molecular mechanisms underlying the effects of SETD2 loss. Functional rescue assays were conducted by supplementing the culture media with serine and glycine. RESULTS Patients with SETD2 loss-of-function mutations or low SETD2 expression showed significantly improved survival. In vitro, SETD2 KD or inhibition reduced cell proliferation and survival while enhancing radiation sensitivity. Transcriptomic profiling revealed marked downregulation of the serine synthesis pathway in SETD2-deficient cells. Notably, exogenous serine and glycine supplementation partially rescued cell viability and reversed the increased radiosensitivity in SETD2 KD cells. CONCLUSION SETD2 loss predicts favorable prognosis in GBM, potentially through metabolic vulnerability induced by suppression of the serine synthesis pathway. These findings highlight a novel therapeutic window by targeting serine metabolism in SETD2-deficient GBM.