Pivotal role of NAMPT in the switch of melanoma cells toward an invasive and drug-resistant phenotype.

In BRAF melanoma cells, a global metabolomic analysis discloses a decrease in nicotinamide adenine dinucleotide (NAD) levels upon PLX4032 treatment that is conveyed by a STAT5 inhibition and a transcriptional regulation of the nicotinamide phosphoribosyltransferase (NAMPT) gene. NAMPT inhibition decreases melanoma cell proliferation both in vitro and in vivo, while forced NAMPT expression renders melanoma cells resistant to PLX4032. NAMPT expression induces transcriptomic and epigenetic reshufflings that steer melanoma cells toward an invasive phenotype associated with resistance to targeted therapies and immunotherapies.