Drug-induced reorganisation of lipid metabolism limits the therapeutic efficacy of ponatinib in glioma stem cells

Simple item page
dc.contributor.authorAldaz Donamaría, Paula
dc.contributor.authorOlías Arjona, Ana
dc.contributor.authorLasheras Otero, Irene
dc.contributor.authorAusín, Karina
dc.contributor.authorRedondo Muñoz, Marta
dc.contributor.authorWellbrock, Claudia
dc.contributor.authorSantamaría Martínez, Enrique
dc.contributor.authorFernández Irigoyen, Joaquín
dc.contributor.authorArozarena Martinicorena, Imanol
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.contributor.funderGobierno de Navarra / Nafarroako Gobernua
dc.date.accessioned2024-10-23T18:07:13Z
dc.date.available2024-10-23T18:07:13Z
dc.date.issued2024-05-29
dc.date.updated2024-10-23T17:29:24Z
dc.description.abstractThe standard of care for glioblastoma (GBM) involves surgery followed by adjuvant radio- and chemotherapy, but often within months, patients relapse, and this has been linked to glioma stem cells (GSCs), self-renewing cells with increased therapy resistance. The identification of the epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) as key players in gliomagenesis inspired the development of inhibitors targeting these tyrosine kinases (TKIs). However, results from clinical trials testing TKIs have been disappointing, and while the role of GSCs in conventional therapy resistance has been extensively studied, less is known about resistance of GSCs to TKIs. In this study, we have used compartmentalised proteomics to analyse the adaptive response of GSCs to ponatinib, a TKI with activity against PDGFR. The analysis of differentially expressed proteins revealed that GSCs respond to ponatinib by broadly rewiring lipid metabolism, involving fatty acid beta-oxidation, cholesterol synthesis, and sphingolipid degradation. Inhibiting each of these metabolic pathways overcame ponatinib adaptation of GSCs, but interrogation of patient data revealed sphingolipid degradation as the most relevant pathway in GBM. Our data highlight that targeting lipid metabolism, and particularly sphingolipid degradation in combinatorial therapies, could improve the outcome of TKI therapies using ponatinib in GBM.en
dc.description.sponsorshipThis research was funded by the Instituto de Salud Carlos III-FEDER through [grant number PI22/01982] to I.A., [grant number PT17/0019/009] to J.F.-I. I.A. also acknowledges support through Miguel Servet II fellowship [CPII20/00011]. The Industry Department of the Government of Navarra, Spain, funded work through [grant number PI1054] to I.A. and [grant number PI1059] to E.S. The Proteomics Platform of Navarrabiomed is member of Proteored (PRB3-ISCIII). P.A: is funded by a Sara Borrell fellowship from the Instituto de Salud Carlos III.
dc.format.mimetypeapplication/pdfen
dc.identifier.citationAldaz, P., Olias-Arjona, A., Lasheras-Otero, I., Ausin, K., Redondo-Muñoz, M., Wellbrock, C., Santamaria, E., Fernandez-Irigoyen, J., Arozarena, I. (2024) Drug-induced reorganisation of lipid metabolism limits the therapeutic efficacy of ponatinib in glioma stem cells. Pharmaceutics, 16(6), 1-19. https://doi.org/10.3390/pharmaceutics16060728.
dc.identifier.doi10.3390/pharmaceutics16060728
dc.identifier.issn1999-4923
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/52367
dc.language.isoeng
dc.publisherMDPI
dc.relation.ispartofPharmaceutics 2024, 16(6), 728
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica, Técnica y de Innovación 2021-2023/PI22%2F01982/ES/
dc.relation.publisherversionhttps://doi.org/10.3390/pharmaceutics16060728
dc.rights© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCholesterolen
dc.subjectGlioblastomaen
dc.subjectGlioma stem cellen
dc.subjectLipid metabolismen
dc.subjectPonatiniben
dc.subjectSphingolipidsen
dc.titleDrug-induced reorganisation of lipid metabolism limits the therapeutic efficacy of ponatinib in glioma stem cellsen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication77c888ac-462b-41e5-ba32-7f4272102203
relation.isAuthorOfPublicationc447bde5-7baf-4708-b62a-2b8a15356673
relation.isAuthorOfPublicationabacfd17-2b93-4d99-bae2-52053d57401e
relation.isAuthorOfPublication86d1b76e-4790-40b1-a3ec-72331c5c6199
relation.isAuthorOfPublication.latestForDiscovery77c888ac-462b-41e5-ba32-7f4272102203

Files

Original bundle
Now showing 1 - 2 of 2
Thumbnail Image
Name:
Aldaz_DrugInduced.pdf
Size:
5.45 MB
Format:
Adobe Portable Document Format
Download
Thumbnail Image
Name:
Aldaz_DrugInduced_MatCompl.pdf
Size:
1.08 MB
Format:
Adobe Portable Document Format
Download
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.71 KB
Format:
Item-specific license agreed to upon submission
Description:
Download

Collections

Artículos de revista DCS - OZS Aldizkari artikuluak
Artículos de revista - Aldizkari artikuluak