OSS SEMINAR - CHEVET Éric - Research Director U1242_OSS UNIT - IRE1-dependent lipid metabolism control and resistance to temozolomide in glioblastoma - Centre De Lutte Contre Le Cancer Eugène Marquis

IRE1-dependent lipid metabolism control and resistance to temozolomide in glioblastoma

Dr CHEVET Éric

Research Director

INSERM U1242_OSS UNIT DIRECTOR

Abstract
Glioblastoma (GB) is the most aggressive primary tumor of the brain with a survival of about 15 months. The current standard of care (SOC) has remained marginally unchanged since 2005, thus highlighting the need for novel therapeutic approaches. We previously identified IRE1, a sensor of the Unfolded Protein Response, as a promising therapeutic target in GB. To investigate the clinical potential of IRE1 pharmacologic inhibition, we assessed the effect of two IRE1 inhibitors in two syngeneic models of GB. We demonstrated on both models that the inhibition of IRE1 sensitized GB to the SOC, leading to an increased mouse survival. Consistently, whole exome sequencing showed that mutation burden and profiles in tumors treated by the SOC exhibited higher signs of defective DNA repair mechanisms when administered with IRE1 inhibitors. Hence, IRE1 inhibition might reduce DNA repair ability in GB cells therefore sensitizing them to genotoxic agents. RNAseq analyses of B4.7-treated tumors, which conferred a survival benefit even as monotherapy, strongly suggested a link between IRE1 signaling and glycerolipid metabolism, through the diacylglycerol kinase iota (DGKI). The impact of IRE1 activity over DGKI was validated across multiple models, and within a human GB cohort, where Dgki expression levels stratified patient survival, implying that modulating lipid metabolism through IRE1 inhibition may improve prognosis.