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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biphenyl Compounds / administration & dosage*
  • Biphenyl Compounds / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Down-Regulation
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Synergism
  • Enzyme Inhibitors / administration & dosage*
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Lysophospholipids / metabolism
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / metabolism
  • Mice
  • Nitrophenols / administration & dosage*
  • Nitrophenols / pharmacology
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Piperazines / administration & dosage
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins B-raf / genetics
  • Receptors, Lysosphingolipid / metabolism*
  • Sphingolipids / blood*
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism
  • Sphingosine-1-Phosphate Receptors
  • Sulfonamides / administration & dosage*
  • Sulfonamides / pharmacology
  • Vemurafenib
  • Xenograft Model Antitumor Assays

Substances

  • ABT-737
  • Biphenyl Compounds
  • Enzyme Inhibitors
  • Lysophospholipids
  • Nitrophenols
  • Piperazines
  • Receptors, Lysosphingolipid
  • S1PR1 protein, human
  • Sphingolipids
  • Sphingosine-1-Phosphate Receptors
  • Sulfonamides
  • sphingosine-1-phosphate receptor-3, human
  • Vemurafenib
  • sphingosine 1-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Sphingosine