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Targeting the Sphingosine 1-Phosphate Axis Exerts Potent Antitumor Activity in BRAFi-Resistant Melanomas

dc.rights.licenseopenen_US
dc.contributor.authorGARANDEAU, David
dc.contributor.authorNOUJARÈDE, Justine
dc.contributor.authorLECLERC, Justine
dc.contributor.authorIMBERT, Caroline
dc.contributor.authorGARCIA, Virginie
hal.structure.identifierBiologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases
dc.contributor.authorBATS, Marie-Lise
dc.contributor.authorRAMBOW, Florian
dc.contributor.authorGILHODES, Julia
dc.contributor.authorFILLERON, Thomas
dc.contributor.authorMEYER, Nicolas
dc.contributor.authorBRAYER, Stéphanie
dc.contributor.authorARCUCCI, Silvia
dc.contributor.authorTARTARE-DECKERT, Sophie
dc.contributor.authorSÉGUI, Bruno
dc.contributor.authorMARINE, Jean-Christophe
dc.contributor.authorLEVADE, Thierry
dc.contributor.authorBERTOLOTTO, Corine
dc.contributor.authorANDRIEU-ABADIE, Nathalie
dc.date.accessioned2020-11-16T12:27:13Z
dc.date.available2020-11-16T12:27:13Z
dc.date.issued2019-02
dc.identifier.issn1535-7163, 1538-8514en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/14026
dc.description.abstractEnAbstract BRAF inhibitors (BRAFi) are used to treat patients with melanoma harboring the V600E mutation. However, resistance to BRAFi is inevitable. Here, we identified sphingosine 1-phosphate (S1P) receptors as regulators of BRAFV600E-mutant melanoma cell-autonomous resistance to BRAFi. Moreover, our results reveal a distinct sphingolipid profile, that is, a tendency for increased very long-chain ceramide species, in the plasma of patients with melanoma who achieve a response to BRAFi therapy as compared with patients with progressive disease. Treatment with BRAFi resulted in a strong decrease in S1PR1/3 expression in sensitive but not in resistant cells. Genetic and pharmacologic interventions, that increase ceramide/S1P ratio, downregulated S1PR expression and blocked BRAFi-resistant melanoma cell growth. This effect was associated with a decreased expression of MITF and Bcl-2. Moreover, the BH3 mimetic ABT-737 improved the antitumor activity of approaches targeting S1P-metabolizing enzymes in BRAFi-resistant melanoma cells. Collectively, our findings indicate that targeting the S1P/S1PR axis could provide effective therapeutic options for patients with melanoma who relapse after BRAFi therapy.
dc.language.isoENen_US
dc.subjectArticle RECHERCHE
dc.title.enTargeting the Sphingosine 1-Phosphate Axis Exerts Potent Antitumor Activity in BRAFi-Resistant Melanomas
dc.typeArticle de revueen_US
dc.identifier.doi10.1158/1535-7163.MCT-17-1141en_US
dc.subject.halSciences du Vivant [q-bio]/Médecine humaine et pathologieen_US
bordeaux.journalMolecular Cancer Therapeuticsen_US
bordeaux.page289–300en_US
bordeaux.volume18en_US
bordeaux.hal.laboratoriesBiologie des maladies cardiovasculaires - U1034en_US
bordeaux.issue2en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-03194448
hal.version1
hal.date.transferred2021-04-09T13:17:50Z
hal.exporttrue
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