Nicotinic acid-free diet and NAPRT inhibitors as a means to sensitize cancer cells to NAMPT inhibitors

Depleting NAD levels in tumors by interrupting their NAD-biosynthetic routes is an attractive anti-cancer strategy. Yet, suppressing the predominant NAD-producing salvage pathway by nicotinamide phosphoribosyltransferase (NAMPT) inhibitors failed in clinical trials, indicating that tumors can exploit alternative NAD-biosynthetic routes to escape NAMPT blockade. In this regard, the contribution of the Preiss-Handler (PH) pathway to NAD production in tumors is gaining great momentum. This pathway utilizes nicotinic acid (NA) as a substrate, which can be obtained from the diet or the gut microbiome. Herein, we demonstrate that blocking the PH pathway with an NA-free diet restored the activity of the NAMPT inhibitor FK866 in an ovarian cancer xenograft model. This combined intervention significantly reduced tumor volumes, blunted NAD levels, and impaired the energy status and metabolic activity of the tumors, while showing no systemic toxicity. In addition, combining an NA-free diet with antibiotics (to eliminate microbiota-derived NA) delayed tumor progression in the absence of NAMPT inhibitors. Furthermore, we also aimed at identifying new inhibitors to the rate-limiting enzyme of the PH pathway nicotinic acid phosphoribosyltransferase (NAPRT). We took advantage of in silico screening techniques and were able to annotate and characterize two NAPRT inhibitors that showed anti-cancer efficacy at micromolar concentrations while possessing favorable drug-like profiles. Since some NAMPT inhibitors are being currently evaluated in clinical trials, this work provides a rationale to couple NA-free diets or NAPRT inhibitors with NAMPT inhibitors in cancer patients.