TMET-40. Proneural Glioblastomas Exhibit Altered Lipid Metabolism That Promotes Susceptibility to Non-Canonical Cell Death

Abstract Glioblastomas (GBMs) are highly resistant to therapies (e.g., radiation, chemotherapy therapy) targeting canonical apoptotic pathways. Emerging evidence suggests that non-canonical, lipid-mediated cell death mechanisms - such as ferroptosis – may offer therapeutic opportunities in genetically defined GBM subsets. Here, we identify a distinct, palmitate (16:0)-dependent form of non-canonical cell death induced by the clinical-stage compound Tegavivint. Tegavivint exhibited significant cell death across several apoptotic refractory glioma models. However, response was heterogeneous and correlated with a lipidomic signature enriched in palmitate-containing phospholipids. Notably, genetic alterations did not predict sensitivity, however, transcriptomic profiling revealed that tumors with high OLIG2 expression marked Tegavivint-responsive tumors. Ectopic OLIG2 expression in resistant lines conferred sensitivity to Tegavivint increased levels of 16:0 phospholipids, linking the proneural glioma subtype to metabolic susceptibility. Furthermore, pharmacologic inhibition of protein palmitoylation significantly reduced Tegavivint-induced cell death, suggesting a mechanistic role for protein palmitoylation and this novel cell death pathway. These findings uncover a previously unrecognized, lipid-driven vulnerability in GBMs and provide a rationale for targeting palmitate -associated non-canonical cell death as a therapeutic strategy.