Abstract
Metastatic melanoma carrying BRAF mutations represent a still unmet medical need as success of BRAF inhibitors is limited by development of resistance. Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme in NAD biosynthesis. An extracellular form (eNAMPT) possesses cytokine-like functions and is up-regulated in inflammatory disorders, including cancer. Here we show that eNAMPT is actively released in culture supernatants of melanoma cell lines. Furthermore, cells that become resistant to BRAF inhibitors (BiR) show a significant increase of eNAMPT levels. Plasma from mice xenografted with BiR cell lines contain higher eNAMPT levels compared to tumor-free animals. Consistently, eNAMPT levels are elevated in 113 patients with BRAF-mutated metastatic melanoma compared to 50 with localized disease or to 38 healthy donors, showing a direct correlation with markers of tumor burden, such as LDH, or aggressive disease (such as PD-L1). eNAMPT concentrations decrease in response to therapy with BRAF/MEK inhibitors, but increase again at progression, as inferred from the serial analysis of 50 patients. Lastly, high eNAMPT levels correlate with a significantly shorter overall survival.Our findings suggest that eNAMPT is a novel marker of tumor burden and response to therapy in patients with metastatic melanoma carrying BRAF mutations.
Highlights
NAD is a vital molecule in all organisms and a major component of both energy and signal transduction processes [1, 2]
ENAMPT is present in melanoma cell line supernatants and in melanoma xenografts, increasing upon acquisition of resistance to BRAF inhibitors (BRAFi)
By using a commercially available sandwich Enzyme-Linked Immunosorbent Assay (ELISA) assay, we confirmed variable levels of eNAMPT in conditioned media from 5 BRAFwt and 7 BRAF-mutated (V600E) melanoma cell lines with no significant differences based on the presence of the BRAF (V600E) mutation (Figure 1A)
Summary
NAD is a vital molecule in all organisms and a major component of both energy and signal transduction processes [1, 2]. Nicotinamide, which is released by NAD-metabolizing enzymes, is the major source to maintain NAD levels, linking substrate and product in a functional loop [3,4,5,6]. Nicotinamide is recycled back to NAD via a two-step pathway involving nicotinamide conversion to NMN, and NMN adenylation to NAD. The enzyme nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first and rate-limiting reaction of the pathway [7, 8]. Beside this canonical intracellular activity, NAMPT was discovered to be present in the extracellular milieu where it exerts cytokine/adipokine-like actions [eNAMPT, aka pre-B cell colony enhancing factor (PBEF) or Visfatin] [9]. Even if the mechanisms underlying eNAMPT secretion remain unknown, there seems to be a direct correlation with intracellular (i) NAMPT concentration [8, 17, 18]
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