NAMPT Inhibition in Neuroendocrine Cancers and the Role of NAD+ Precursors: Preclinical Findings

Synopsis

Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme that helps cancer cells make NAD+, a molecule essential for energy production and survival. Drugs that block NAMPT (NAMPT inhibitors) can kill cancer cells, but their effectiveness varies. This study found that neuroendocrine cancers—a subtype of lung and prostate tumors—are especially sensitive to NAMPT inhibition because they rely heavily on this pathway for NAD+ production. However, in lab experiments, very high (supra-physiological) levels of nicotinic acid (NA) or nicotinamide riboside (NR) can rescue cells from NAMPT inhibitor–induced NAD+ loss, though such levels are rarely reached in living organisms. In mouse models, reducing nicotinic acid riboside (NAR) levels through dietary restriction or genetic modification made NAMPT inhibitors far more effective, leading to synthetic lethality—a state where the combined treatment kills tumor cells completely. The findings suggest that combining NAMPT-targeted therapy with dietary control of niacin sources could offer a powerful, metabolism-based treatment strategy for neuroendocrine cancers.

Journal

Nature Communications