TMIC-79. IDH1-R132H REWIRES AUTOPHAGY IN THE GLIOMA MICROENVIRONMENT TO FACILITATE TUMOR PROGRESSION AND RESPONSE TO RADIATION

Abstract Gliomas are primary brain tumors with a poor prognosis. IDH1R132H exhibits a gain of function mutation leading to 2-hydroxyglutarate (2HG) production. We previously demonstrated, 2-HG mediated epigenetic rewiring is associated with better prognosis and its presence impacts several cellular functions including immune responses and enhanced DNA-damage response in IDH1R132H gliomas harboring p53 and ATRX loss-of-function mutations. Also, IDH1R132H elicits metabolic reprogramming which implies that IDH1R132H could modify the energetic state of gliomas with consequences in tumor biology and therapeutic responses. In this study, RNA-seq and ChIP-seq data revealed human and mouse IDH1R132H gliomas have downmodulated gene ontologies related to mitochondrial metabolism. This was paralleled by a decrease in glycolysis, rendering autophagy as a source of energy for IDH1R132H glioma cells. We also found that IDH1R132H-neurospheres have decreased levels of oxygen consumption and extracellular acidification rates, characteristic of an autophagic/quiescent state when compared to IDH1WT-neurospheres. Analysis of the autophagy pathway revealed that both human and mouse IDH1R132H gliomas have increased expression of pULK1-S555, pATG4b-S383, enhanced conversion of LC3I to LC3II, and decreased expression of pULK1-S757, p62 indicating that IDH1R132H cells have augmented autophagy activity compared to IDH1WT cells. Blocking autophagy selectively impairs the growth of IDH1R132H glioma cells in vitro. Targeting autophagy by systemic administration of synthetic protein nanoparticles packaged with siRNA targeting Atg7 sensitized IDH1R132H glioma cells to radiation-induced cell death, resulting in tumor regression, long-term survival, and immunological memory when used in combination with irradiation. Our results thus indicate that the metabolic changes in IDH1R132H glioma cells lead to compromised mitochondrial functions and increased autophagic activity which contributes to their radioresistance, representing a novel therapeutic target for IDH1R132H cells. *Corresponding author: Maria G. Castro: [email protected] Equal contributions: KB-FN-AM-AM-CT Funding: This work was supported by National Institutes of Health/National Institute of Neurological Disorders & Stroke (NIH/NINDS) Grants: [R37-NS094804, R01-NS122165, R21-NS123879-01 awarded to MGC]; [R01-NS122378, R01-NS122234 awarded to PRL], Ian’s Friends & Chad Tough Foundation.