Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a novel marker for patients with BRAF-mutated metastatic melanoma
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Valentina Audrito1,2, Antonella Managò1,2, Federica Zamporlini3, Eliana Rulli4, Federica Gaudino1,2, Gabriele Madonna5, Stefania D'Atri6, Gian Carlo Antonini Cappellini7, Paolo Antonio Ascierto5, Daniela Massi8, Nadia Raffaelli3, Mario Mandalà9,* and Silvia Deaglio1,2,*
1Department of Medical Sciences, University of Turin, Turin, Italy
2Italian Institute for Genomic Medicine, Turin, Italy
3Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy
4Statistics Unit Methodology for Clinical research Laboratory, Oncology Department, IRCCS, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
5Melanoma, Cancer Immunotherapy and Innovative Therapies O.U., Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Napoli, Italy
6Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy
7Department of Oncology and Dermatological Oncology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy
8Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
9Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy
Keywords: metastatic melanoma; tumor marker; prognosis; resistance to therapy; NAMPT
Received: October 19, 2017 Accepted: February 28, 2018 Published: April 10, 2018
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.
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