GLP1R agonists and vorasidenib converge on peroxynitrite-mediated cytotoxicity in mutant IDH glioma

Abstract

Mutations in isocitrate dehydrogenase 1 or 2 (mIDH) generate the oncometabolite D-2-hydroxyglutarate that drives tumorigenesis in a distinct molecular class of gliomas. The mIDH inhibitor vorasidenib slows tumor growth, but disease progression remains a challenge, identifying a need for strategies that deepen and prolong therapeutic response. Here, we show that glucagon-like peptide-1R (GLP1R) agonists synergize with vorasidenib in patient-derived and murine models of mIDH glioma. Mechanistically, GLP1R agonists activate cAMP-protein kinase A signaling and induce nitric oxide synthase 1-dependent nitric oxide production in mIDH glioma cells. Nitric oxide inhibits aconitase and ribonucleotide reductase via S-nitrosylation, thereby disrupting the tricarboxylic acid cycle, depleting deoxyribonucleotides, blocking DNA synthesis, and exerting a cytostatic inhibition of tumor cell proliferation. Concomitantly, vorasidenib relieves D-2HG-driven suppression of pyruvate dehydrogenase, thereby increasing mitochondrial superoxide production and suppressing proliferation without cytotoxicity. When combined, GLP1R agonist-induced nitric oxide and vorasidenib-induced superoxide converge to generate peroxynitrite, which damages lipids and DNA, and triggers apoptosis in mIDH glioma cells. Combining a GLP1R agonist with vorasidenib recapitulates these metabolic and pharmacodynamic effects in mice bearing intracranial mIDH tumors, induces tumor regression, and significantly prolongs survival relative to each monotherapy in vivo. Collectively, our studies demonstrate that GLP1R agonism and mIDH inhibition induce distinct alterations in mitochondrial redox metabolism that converge to produce synergistic cytotoxicity and provide a mechanistic basis for clinical evaluation of this therapeutic strategy in patients with mIDH glioma.