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L-asparaginase anti-tumor activity in pancreatic cancer is dependent on its glutaminase activity and resistance is mediated by glutamine synthetase

dc.rights.licenseopenen_US
dc.contributor.authorBLACHIER, Jonathan
dc.contributor.authorCLERET, Aurore
dc.contributor.authorGUERIN, Nathalie
dc.contributor.authorGIL, Clara
dc.contributor.authorFANJAT, Jean-Marc
dc.contributor.authorTAVERNIER, Florian
dc.contributor.authorVIDAULT, Laura
dc.contributor.authorGALLIX, Fanny
dc.contributor.authorRAMA, Nicolas
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorROSSIGNOL, Rodrigue
dc.contributor.authorPIEDRAHITA, Diana
dc.contributor.authorANDRIVON, Aurely
dc.contributor.authorCHÂLONS-COTTAVOZ, Marie
dc.contributor.authorAGUERA, Karine
dc.contributor.authorGAY, Fabien
hal.structure.identifierERYTECH Pharma
dc.contributor.authorHORAND, Francoise
dc.contributor.authorLAPERROUSAZ, Bastien
dc.date.accessioned2023-11-27T09:51:13Z
dc.date.available2023-11-27T09:51:13Z
dc.date.issued2023-05-15
dc.identifier.issn1090-2422en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/186152
dc.description.abstractEnl-Asparaginase is a cornerstone of acute lymphoblastic leukemia (ALL) therapy since lymphoblasts lack asparagine synthetase (ASNS) and rely on extracellular asparagine availability for survival. Resistance mechanisms are associated with increased ASNS expression in ALL. However, the association between ASNS and l-Asparaginase efficacy in solid tumors remains unclear, thus limiting clinical development. Interestingly, l-Asparaginase also has a glutaminase co-activity that is crucial in pancreatic cancer where KRAS mutations activate glutamine metabolism. By developing l-Asparaginase-resistant pancreatic cancer cells and using OMICS approaches, we identified glutamine synthetase (GS) as a marker of resistance to l-Asparaginase. GS is the only enzyme able to synthesize glutamine, and its expression also correlates with l-Asparaginase efficacy in 27 human cell lines from 11 cancer indications. Finally, we further demonstrated that GS inhibition prevents cancer cell adaptation to l-Asparaginase-induced glutamine starvation. These findings could pave the way to the development of promising drug combinations to overcome l-Asparaginase resistance.
dc.language.isoENen_US
dc.subjectDrug resistance
dc.subjectGlutamine
dc.subjectGlutamine synthetase
dc.subjectL-asparaginase
dc.subjectPancreatic cancer
dc.title.enL-asparaginase anti-tumor activity in pancreatic cancer is dependent on its glutaminase activity and resistance is mediated by glutamine synthetase
dc.title.alternativeExp Cell Resen_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1016/j.yexcr.2023.113568en_US
dc.subject.halSciences du Vivant [q-bio]/Génétiqueen_US
dc.identifier.pubmed36967104en_US
bordeaux.journalExperimental Cell Researchen_US
bordeaux.page113568en_US
bordeaux.volume426en_US
bordeaux.hal.laboratoriesMaladies Rares : Génétique et Métabolisme (MRGM) - UMR 1211en_US
bordeaux.issue2en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcepubmed
hal.identifierhal-04308691
hal.version1
hal.date.transferred2023-11-27T09:51:16Z
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exporttrue
workflow.import.sourcepubmed
dc.rights.ccPas de Licence CCen_US
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