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.
Highlights
Changes in lipid profiles are often associated with an altered metabolic phenotype in tumor cells, which has been recognized as a hallmark of cancers [1]
To test whether sphingosine 1-phosphate (S1P)-dependent signaling pathways are related to the resistance of melanoma cells to BRAF inhibitors (BRAFi), we examined a series of BRAFV600E-mutant melanoma cell lines from the Cancer Cell Line Encyclopedia (CCLE) for which IC50 values, that is, drug concentrations causing 50% growth inhibition, of the selective BRAFi PLX-4720 were available [23]
Bioinformatic analysis revealed that the levels of S1PR1 and S1PR3 transcripts positively correlate with resistance of melanoma cells to the BRAFi (Fig. 1A)
Summary
Changes in lipid profiles are often associated with an altered metabolic phenotype in tumor cells, which has been recognized as a hallmark of cancers [1]. Lipid metabolism can be exploited to develop therapeutic strategies to treat cancer. We recently showed that sphingolipid (SL) metabolism is strongly altered in cutaneous melanoma in favor of metabolites that promote tumor progression [2,3,4]. SLs are a class of lipids, which regulate key biological processes underlying cancer development including cell death, proliferation, migration, and tumor stroma. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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