Format

Send to

Choose Destination
Mol Cancer Ther. 2019 Feb;18(2):289-300. doi: 10.1158/1535-7163.MCT-17-1141. Epub 2018 Nov 27.

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

Author information

1
Université Fédérale de Toulouse Midi-Pyrénées, Université Toulouse III Paul-Sabatier, Inserm, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France.
2
Université Nice Sophia-Antipolis, Inserm, Centre Méditerranéen de Médecine Moléculaire, Nice, France.
3
VIB, Center for the Biology of Disease, Leuven, Belgium.
4
Bureau des essais cliniques, Institut Universitaire du Cancer de Toulouse-Oncopôle, Toulouse, France.
5
Service de Dermatologie-Oncologie, Institut Universitaire du Cancer de Toulouse-Oncopôle, Toulouse, France.
6
Laboratoire de Biochimie Métabolique, CHU Toulouse, France.
7
Université Fédérale de Toulouse Midi-Pyrénées, Université Toulouse III Paul-Sabatier, Inserm, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France. nathalie.andrieu@inserm.fr.
#
Contributed equally

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.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center