Journal
MOLECULAR CANCER THERAPEUTICS
Volume 18, Issue 2, Pages 289-300Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-17-1141
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Funding
- INSERM
- Paul Sabatier University
- Ligue Nationale Contre le Cancer [EL2013-5 LEVADE]
- Societe Francaise de Dermatologie
- LNCC
- Association pour la Recherche contre le Cancer
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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 BRAF(V600E)-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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