Targeting the sphingosine 1-phosphate axis exerts potent antitumor activity in BRAFi-resistant melanomas

BRAF inhibitors (BRAFi) are used to treat melanoma patients 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, i.e. a tendency for increased very long-chain ceramide species, in the plasma of melanoma patients who achieve a response to BRAFi therapy as compared to 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 melanoma patients who relapse after BRAFi therapy.