Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a novel marker for patients with BRAF-mutated metastatic melanoma

// Valentina Audrito 1, 2 , Antonella Manago 1, 2 , Federica Zamporlini 3 , Eliana Rulli 4 , Federica Gaudino 1, 2 , Gabriele Madonna 5 , Stefania D'Atri 6 , Gian Carlo Antonini Cappellini 7 , Paolo Antonio Ascierto 5 , Daniela Massi 8 , Nadia Raffaelli 3 , Mario Mandala 9, * and Silvia Deaglio 1, 2, * 1 Department of Medical Sciences, University of Turin, Turin, Italy 2 Italian Institute for Genomic Medicine, Turin, Italy 3 Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy 4 Statistics Unit Methodology for Clinical research Laboratory, Oncology Department, IRCCS, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy 5 Melanoma, Cancer Immunotherapy and Innovative Therapies O.U., Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Napoli, Italy 6 Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy 7 Department of Oncology and Dermatological Oncology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy 8 Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy 9 Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy * Shared co-authorship Correspondence to: Silvia Deaglio, email: silvia.deaglio@unito.it ; silvia.deaglio@iigm.it Keywords: metastatic melanoma; tumor marker; prognosis; resistance to therapy; NAMPT Received: October 19, 2017      Accepted: February 28, 2018      Published: April 10, 2018 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.