Nicotinic acid starvation sensitizes nicotinate phosphoribosyltransferase-expressing tumors to nicotinamide phosphoribosyltransferase inhibition

Nicotinamide adenine dinucleotide (NAD + ) biosynthesis underlies many aspects of carcinogenesis. Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), which drives NAD + biosynthesis from nicotinamide (NAM), are promising anticancer agents, but their activity is limited when tumors also express nicotinate phosphoribosyltransferase (NAPRT), a second NAD + -producing enzyme that uses nicotinic acid (NA) as a precursor. 1 , 2 The NAPRT gene is amplified and overexpressed in 25% of ovarian cancers and between 5 and 10% of breast, pancreatic, head & neck, liver, esophageal, and prostate cancers ( https://www.cbioportal.org/ , TCGA-PanCancer-Atlas studies). NAPRT-expressing tumors are addicted to its NAD + -generating activity to support oxidative phosphorylation (OXPHOS), protein synthesis and DNA repair, and to avoid NAD + shortages in response to NAMPT inhibitors. 1 , 2 High NAPRT expression confers poor survival outcomes in different types of cancer, including ovarian, breast, colorectal, and pancreatic cancer ( https://kmplot.com/analysis/ ; https://www.cbioportal.org/ ), underscoring NAPRT’s relevance as a therapeutic target. Given the limited potency and solubility of available NAPRT inhibitors, 2 we tested whether removing NA from the diet, which is a major source of this vitamin, could be used to reduce NAPRT-mediated NAD + production and sensitize tumors to NAMPT inhibition.