Synergistic effects of vemurafenib and fingolimod (FTY720) in vemurafenib‑resistant melanoma cell lines.

Abstract

Vemurafenib, a selective inhibitor of mutated BRAF, is used to treat late‑stage melanoma. However, resistance to vemurafenib is urgently required as it can have fatal consequences. Fingolimod (FTY720), a sphingosine‑1‑phosphate receptor modulator, has been used for the treatment of several malignant neoplasms in clinical trials. The present study investigated the effects of FTY720 and vemurafenib combination treatment on cell death induction, and defined the molecular mechanisms in vemurafenib‑resistant melanoma cells. The combination treatment with FTY720 and vemurafenib reduced cell viability, and the expression of apoptosis‑associated cleaved poly (adenosine diphosphate‑ribose) polymerase (PARP) was increased when compared with treatment with vemurafenib alone in WM‑115 cells, a vemurafenib‑resistant human melanoma cell line. In addition, the protein expression of phosphorylated extracellular signal‑related kinase (ERK) in WM‑115 cells was decreased by this combination treatment. Vemurafenib‑resistant SK‑Mel‑28 cells (R‑SK‑Mel) were established by culturing SK‑Mel‑28 cells, which are the most sensitive to vemurafenib, in the presence of vemurafenib. Similar to WM‑155 cells, the viability of R‑SK‑Mel cells was reduced and the expression of cleaved PARP was increased by the combination treatment with FTY720 and vemurafenib. In addition, the expression of phosphorylated ERK and Akt was also reduced by this treatment. These results suggested that FTY720 and vemurafenib synergistically induced cell death by downregulating proliferation and survival signalling pathways in vemurafenib‑resistant melanoma cells.