Mechanisms of resistance to NAMPT inhibitors in cancer.

A common barrier to the development of effective anticancer agents is the development of drug resistance. This obstacle remains a challenge to successful clinical translation, particularly for targeted agents. Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors represent a clinically applicable drug class that exploits the increased dependence of cancer cells on nicotinamide adenine dinucleotide (NAD⁺), a coenzyme essential to metabolism and other cellular functions. NAMPT catalyzes the rate-limiting step in the NAD⁺ salvage pathway of mammalian cells and is overexpressed in numerous types of cancers. Preclinical research has demonstrated that pharmacological targeting of NAMPT may be an effective strategy against certain cancers, and while several early-phase clinical trials testing NAMPT inhibitors in refractory cancers have been completed, drug resistance is a concern. Preclinical work in a variety of cancer models has demonstrated the emergence of resistance to multiple NAMPT inhibitors through several recurrent mechanisms. This review represents the first article summarizing the current state of knowledge regarding the mechanisms of acquired drug resistance to NAMPT inhibitors with a particular focus on upregulation of the compensatory NAD⁺ production enzymes nicotinate phosphoribosyltransferase (NAPRT) and quinolinate phosphoribosyltransferase (QPRT), acquired mutations in NAMPT, metabolic reprogramming, and altered expression of the ATP-binding cassette (ABC) efflux transporter ABCB1. An understanding of how these mechanisms interact with the biology of each given cancer cell type to predispose to the acquisition of NAMPT inhibitor resistance will be necessary to develop strategies to optimize the use of these agents moving forward.