Autophagy Upregulation in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma Uncovers a Novel Therapeutic Target

Mutant isocitrate dehydrogenase 1 (mIDH1) catalyzes 2-hydroxyglutarate production which leads to epigenetic reprogramming in astrocytomas with TP53/ATRX loss. RNA-seq, scRNA-seq, and ChIP-seq analysis revealed that human and mouse mIDH1 gliomas exhibit downregulated gene ontologies (GOs) related to mitochondrial metabolism and upregulated autophagy-related GOs. Decreased mitochondrial metabolism was accompanied by decreased glycolysis, rendering autophagy a source of energy in mIDH1 gliomas. Mutant IDH1 glioma cells exhibited increased expression of autophagy-related proteins and enhanced LC3 I/II conversion, indicating augmented autophagy. Inhibiting autophagy in vivo by administration of synthetic protein nanoparticles encapsulating ATG7-siRNA sensitized mIDH1 glioma cells to radiation, resulting in tumor regression, long-term survival, and immunological memory. This work uncovered autophagy as a critical pathway for survival in mIDH1 gliomas and its inhibition elicits radiosensitivity in vitro in human and mouse mIDH1 glioma cells, and in vivo in mIDH1 models. Thus, autophagy inhibition emerges as an attractive therapeutic target for mIDH1 gliomas.