Nicotinic acid restriction potentiates NAMPT inhibition in acute myeloid leukemia xenograft models.

Abstract NAMPT, a key enzyme in NAD biosynthesis, is a potential therapeutic target in cancer. Acute myeloid leukemia (AML) is among cancer types exhibiting high NAMPT dependence, and elevated NAMPT activity is implicated in venetoclax resistance. Thus, pharmacological NAMPT inhibitors (NAMPTi) have been developed as a promising therapeutic approach in some cancers. However, our current knowledge of in vivo factors that determine NAMPTi therapeutic efficacy is incomplete. Here, using mouse models we found that NAMPTi efficacy against AML is limited by dietary nicotinic acid (NA). Specifically, NA and nicotinic acid riboside (NAR), an NA-derived metabolite, promoted NAD biosynthesis independent of NAMPT and rescued AML cells from NAMPTi-mediated toxicity in vitro. Importantly, in AML xenograft models, dietary NA restriction, which selectively reduces circulating NAR levels, enhanced antitumor efficacy of NAMPTi and prolonged animal survival. Although the combination treatment caused transient hematological toxicity, peripheral blood cell counts largely recovered after treatment. Our findings highlight systemic NAD precursor metabolism, including NAR, as a determinant of responses to NAMPT-targeted therapies. We conclude that NA restriction may improve the therapeutic efficacy of NAMPT inhibitors in AML.