Thesis Defense - LODE Mathéo

IRE1 inhibition and its synergic effects on the standard of care in glioblastoma : Omics analyses in preclinical mice models

LODE Mathéo

PhD - @OMICS Team - UMR INSERM U1242_OSS

Abstract
Glioblastoma (GB) is the most aggressive primary tumor of the brain with a survival post-diagnosis of about 15 months. Despite decades of intensive research, 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. IRE1 activity correlates with GB aggressiveness, and genetic ablation of IRE1 in tumor cells significantly increases survival in an in vivo model. To investigate the clinical potential of IRE1 pharmacologic inhibition, we assessed the effect of two IRE1 inhibitors (MKC8866 and B4.7) 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 may improve prognosis. Together, our work establishes the functional links between IRE1 signaling, lipid metabolism and DNA repair pathways in vivo and opens new avenues for the modulation of IRE1 signaling as a therapeutic approach in GB and other diseases.
Note: The thesis Defense will be hold in French