Felipe J Núñez, Kaushik Banerjee, Anzar A Mujeeb, Ava Mauser, Claire E Tronrud, Ziwen Zhu, Sadhakshi Raghuram, Maya R Sheth, Jorge Armando Pena Agudelo, Julio Zelaya, Ayman Taher, Padma Kadiyala, Stephen V Carney, Maria B Garcia-Fabiani, Andrea Comba, Mahmoud S Alghamri, Brandon L McClellan, Adam Klaiss, Zeribe C Nwosu, Hanna S Hong, Peter Sajjakulnukit, Tingting Qin, Maureen A Sartor, Mats Ljungman, Joshua D Welch, Shi-Yuan Cheng, Pedro R Lowenstein, Joerg Lahann, Costas A Lyssiotis, Maria G Castro
Mutant isocitrate dehydrogenase 1 (mIDH1) catalyzes 2-hydroxyglutarate (2HG) production which leads to epigenetic reprogramming in astrocytomas with tumor protein p53 (TP53)/α-thalassemia/mental retardation, X-linked (ATRX) loss. RNA-sequencing, single-cell RNA-sequencing, and Chromatin Immunoprecipitation sequencing (ChIP-seq) followed by bioinformatics analysis shows that human and mouse mIDH1 gliomas exhibit downregulated gene ontologies (GOs) related to mitochondrial metabolism and upregulated autophagy-related GOs. Decreased mitochondrial metabolism is accompanied by decreased glycolysis, rendering autophagy as a source of energy in mIDH1 gliomas. Mutant IDH1 glioma cells exhibit increased expression of autophagy-related proteins and enhanced microtubule-associated protein 1 light chain 3 (LC3) I/II conversion, indicating augmented autophagy. Inhibiting autophagy in vivo by administration of synthetic protein nanoparticles (SPNPs) encapsulating autophagy related gene 7 (ATG7) silencing RNA sensitizes mIDH1 glioma cells to radiation, resulting in tumor regression, long-term survival, and immunological memory. This work uncovers 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.