Dataset Information

A novel blood brain barrier-permeable IRE1 inhibitor prevents Glioblastoma relapse in mice

ABSTRACT: Inositol Requiring Enzyme 1 (IRE1) is a bifunctional serine/threonine kinase and endoribonuclease that is a major mediator of the Unfolded Protein Response (UPR) during endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse environmental cues such as hypoxia or nutrient shortage and high metabolic/protein folding demand. To cope with those stresses, cancer cells utilize IRE1 signaling as an adaptive mechanism. Here we report the discovery of novel family of compounds as IRE1 inhibitors identified through a structural exploration of the IRE1 kinase domain. All the inhibitors were tested for their ability to sensitize glioblastoma (GBM) cells to chemotherapy. We show that all molecules identified inhibit IRE1 signaling and sensitize glioblastoma cells to the standard of care chemotherapy temozolomide (TMZ). From these inhibitors we selected one that was able to cross the Brain Blood Barrier (BBB) and evaluated its capacity to inhibit tumor growth and avoid relapse in vivo. These results support the attractiveness of IRE1 as an adjuvant therapeutic target in GBM; a common and wholly fatal diagnosis. In addition, they provide scope for quickly testing IRE1 inhibitor suitability in GBM as adjuvant therapy due to their current status for clinical use.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain, Permanent Cell Line Cell

DISEASE(S): Brain Glioblastoma Multiforme

SUBMITTER: Luc Negroni

LAB HEAD: Eric Chevet

PROVIDER: PXD026908 | Pride | 2023-07-20

REPOSITORIES: Pride

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			Action	DRS
	190719_INCA_CS_01rep01.msf	Msf
	190719_INCA_CS_01rep01.raw	Raw
	190719_INCA_CS_01rep02.msf	Msf
	190719_INCA_CS_01rep02.raw	Raw
	190719_INCA_CS_01rep03.msf	Msf

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Publications

A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment.

Pelizzari-Raymundo Diana D Doultsinos Dimitrios D Pineau Raphael R Sauzay Chloé C Koutsandreas Thodoris T Langlais Timothy T Carlesso Antonio A Gkotsi Elena E Negroni Luc L Avril Tony T Chatziioannou Aristotelis A Chevet Eric E Eriksson Leif A LA Guillory Xavier X

iScience 20230424 5

Inositol-requiring enzyme 1 (IRE1) is a major mediator of the unfolded protein response (UPR), which is activated upon endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues, a stress overcome by relying on IRE1 signaling as an adaptive mechanism. Herein, we report the discovery of structurally new IRE1 inhibitors identified through the structural exploration of its kinase domain. Characterization in <i>in vitro</i> and in cellular models showe ...[more]

PMID: 37216120

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Project description:Glioblastoma multiforme (GBM) is the most aggressive form of brain tumors. Despite radical surgery and radiotherapy supported by chemotherapy, the disease still remains incurable with extremely low median survival rate of 12-15 months from the time of initial diagnosis. The main cause of treatment failure is considered to be the presence of cells that are resistant to such treatment. MicroRNAs (miRNAs) as regulators of gene expression are involved in the tumor pathogenesis, including GBM. MiR-338 is a brain specific miRNA which has been described to target pathways involved in proliferation and differentiation. In our study, miR-338-3p and -5p were differentially expressed in GBM tissue in comparison to non-tumor brain tissue. Overexpression of miR-338-3p with miRNA mimic did not show any changes in proliferation rates in GBM cell lines (A172, T98G, U87MG). On the other hand, pre-miR-338-5p notably decreased proliferation and caused cell cycle arrest. Since radiation is currently the main treatment modality in GBM, we combined overexpression of pre-miR-338-5p with radiation, which led to significantly decreased of cell proliferation, and increased cell cycle arrest and apoptosis in comparison to only irradiated cells. To better elucidate the mechanism of action, we performed gene expression profiling analysis that revealed targets of miR-338-5p being Ndfip1, Rheb, ppp2R5a. These genes have been described to be involved in DNA damage response, proliferation and cell cycle regulation. To our knowledge, this is the first study to describe role of miR-338-5p in GBM and its potential to improve sensitivity of GBM to radiation. Study was performed on three glioblastoma multiforme cell lines A172, T98G and U87MG. This experiment was performed on Affymetrix GeneChip Human Gene ST 1.0 to elucidate the targets of miRNA-338-5p. Cell lines were seeded 24 hours prior transfection. After transfection with pre-miR338-5p or negative control cell were cultured for 24 hours and harvested. RNA was isolated using MirVana miRNA Isolation Kit (Ambion, USA) and checked for RNA integrity by Bioanalyzer 2100 and purity by ratios 260/280>1.8 and 260/230>1.8 by Nanodrop2000.