Oncotarget

Research Papers:

A pancreatic ductal adenocarcinoma subpopulation is sensitive to FK866, an inhibitor of NAMPT

Marine Barraud, Jonathan Garnier, Celine Loncle, Odile Gayet, Charlotte Lequeue, Sophie Vasseur, Benjamin Bian, Pauline Duconseil, Marine Gilabert, Martin Bigonnet, Aurélie Maignan, Vincent Moutardier, Stephane Garcia, Olivier Turrini, Jean-Robert Delpero, Marc Giovannini, Philippe Grandval, Mohamed Gasmi, Mehdi Ouaissi, Veronique Secq, Flora Poizat, Nicolas Guibert, Juan Iovanna and Nelson Dusetti _

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Oncotarget. 2016; 7:53783-53796. https://doi.org/10.18632/oncotarget.10776

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Abstract

Marine Barraud1,*, Jonathan Garnier1,*, Celine Loncle1, Odile Gayet1, Charlotte Lequeue1, Sophie Vasseur1, Benjamin Bian1, Pauline Duconseil1, Marine Gilabert1, Martin Bigonnet1, Aurélie Maignan1 Vincent Moutardier1,2,5, Stephane Garcia1,2, Olivier Turrini1,3, Jean-Robert Delpero3, Marc Giovannini3, Philippe Grandval4, Mohamed Gasmi2,5, Mehdi Ouaissi4, Veronique Secq2, Flora Poizat3, Nicolas Guibert6, Juan Iovanna1, Nelson Dusetti1

1Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France

2Hôpital Nord, Marseille, France

3Institut Paoli-Calmettes, Marseille, France

4Hôpital de la Timone, Marseille, France

5CIC1409, AP-HM - Nord University Hospital, Aix-Marseille University, Marseille, France

6Hospices Civils de Lyon, Lyon, France

*These authors have contributed equally to this work

Correspondence to:

Nelson Dusetti, email: nelson.dusetti@inserm.fr

Juan Iovanna, email: juan.iovanna@inserm.fr

Keywords: pancreatic cancer, NAMPT, FK866, chemotherapy

Received: February 03, 2016    Accepted: July 09, 2016    Published: July 22, 2016

ABSTRACT

Treating pancreatic cancer is extremely challenging due to multiple factors, including chemoresistance and poor disease prognosis. Chemoresistance can be explained by: the presence of a dense stromal barrier leading to a lower vascularized condition, therefore limiting drug delivery; the huge intra-tumoral heterogeneity; and the status of epithelial-to-mesenchymal transition. These factors are highly variable between patients making it difficult to predict responses to chemotherapy. Nicotinamide phosphoribosyl transferase (NAMPT) is the main enzyme responsible for recycling cytosolic NAD+ in hypoxic conditions. FK866 is a noncompetitive specific inhibitor of NAMPT, which has proven anti-tumoral effects, although a clinical advantage has still not been demonstrated. Here, we tested the effect of FK866 on pancreatic cancer-derived primary cell cultures (PCCs), both alone and in combination with three different drugs typically used against this cancer: gemcitabine, 5-Fluorouracil (5FU) and oxaliplatin. The aims of this study were to evaluate the benefit of drug combinations, define groups of sensitivity, and identify a potential biomarker for predicting treatment sensitivity. We performed cell viability tests in the presence of either FK866 alone or in combination with the drugs above-mentioned. We confirmed both inter- and intra-tumoral heterogeneity. Interestingly, only the in vitro effect of gemcitabine was influenced by the addition of FK866. We also found that NAMPT mRNA expression levels can predict the sensitivity of cells to FK866. Overall, our results suggest that patients with tumors sensitive to FK866 can be identified using NAMPT mRNA levels as a biomarker and could therefore benefit from a co-treatment of gemcitabine plus FK866.


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