Molecular Mechanisms and Insights into the Nampt Inhibitor (FK866) Resistance in Cancers

Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ biosynthesis from nicotinamide, is one of the major factors regulating cell metabolism and NAMPT is considered a promising target for treating cancer. The NAMPT inhibitor (FK866) has exhibited anticancer activity in several preclinical models by depleting NAD+ and ATP levels. Recently, we showed that FK866 induced translation arrest through the activation of 5’AMP-activated protein kinase (AMPK), inhibition of mTOR/4EBP1 signaling, and phosphorylation of EIF2a in leukemia cells. Cancer drug resistance continues to be a major challenge in medical oncology. Deregulated cellular metabolism is linked to such cell resistance. Indeed, both components of the glycolytic and mitochondrial pathways are involved in altered metabolism conferring chemoresistance in several cancers. In this study, we developed FK866-resistant models in T- lymphoblastic leukemia (CCRF-CEM) and breast cancer (MDA-MB231) cell lines to investigate the molecular mechanism of pharmacoresistance to NAMPT inhibitor (FK866). Our resistant cells were not inhibited at the translational level by FK866 and the drug-induced metabolic adaptations of the resistant cells conferred an advantage to counteract FK866 toxicity. We reveal a molecular mechanism by which FK866 resistant CCRF-CEM cells utilize alternative sources for NAD production to fuel cell metabolism, and metabolic reprogramming was associated to the drug resistance. Importantly, the FK866- induced metabolic alteration was overcome by the co-administration of FK866 with compounds targeting metabolism, thereby rendering a synergistic outcome and restoring cell susceptibility towards FK866. We highlighted a molecular target that favors acquiring of resistance in leukemia and breast cancer cells. In conclusion, targeting metabolic alterations associated with drug resistance to FK866 may open up unexplored opportunities for the development of new therapeutic strategies as a combinatorial treatment for cancer.