Targeting the Sphingosine 1-Phosphate Axis Exerts Potent Antitumor Activity in BRAFi-Resistant Melanomas - Biology of Cardiovascular Diseases Accéder directement au contenu
Article Dans Une Revue Molecular Cancer Therapeutics Année : 2019

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

David Garandeau
  • Fonction : Auteur
Justine Noujarède
  • Fonction : Auteur
Justine Leclerc
  • Fonction : Auteur
Caroline Imbert
  • Fonction : Auteur
Virginie Garcia
  • Fonction : Auteur
Florian Rambow
  • Fonction : Auteur
Julia Gilhodes
  • Fonction : Auteur
Thomas Filleron
Nicolas Meyer
Stéphanie Brayer
  • Fonction : Auteur
  • PersonId : 765129
  • IdRef : 184582652
Silvia Arcucci
Sophie Tartare-Deckert
  • Fonction : Auteur
Bruno Ségui
  • Fonction : Auteur
Jean-Christophe Marine
  • Fonction : Auteur
Thierry Levade
  • Fonction : Auteur
Corine Bertolotto
  • Fonction : Auteur
Nathalie Andrieu-Abadie

Résumé

Abstract 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.

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Dates et versions

hal-03194448 , version 1 (09-04-2021)

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David Garandeau, Justine Noujarède, Justine Leclerc, Caroline Imbert, Virginie Garcia, et al.. Targeting the Sphingosine 1-Phosphate Axis Exerts Potent Antitumor Activity in BRAFi-Resistant Melanomas. Molecular Cancer Therapeutics, 2019, 18 (2), pp.289-300. ⟨10.1158/1535-7163.MCT-17-1141⟩. ⟨hal-03194448⟩

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