Targeting NAD metabolism in neuroendocrine carcinoma

NAD is an important metabolite that functions as a cofactor in various metabolic reactions, and its biosynthesis is known to be upregulated during malignant transformation. The NAD salvage, in which NAMPT is a rate-limiting enzyme, is a predominant pathway for NAD synthesis in most tissues including cancer. However, less is known about how cancer sensitivity against NAMPT inhibition (NAMPTi) is dictated. Here we report that lung and prostate neuroendocrine carcinomas (NECs) are extremely vulnerable to NAMPTi and that the therapeutic effect of NAMPTi is markedly enhanced by dietary restriction of the NAD precursor, niacin. We found that de novo NAD synthesis is inactivated during neuroendocrine differentiation of tumor cells, leading to a high dependence of NEC cells on NAD salvage. Further investigations in mouse transplantation models showed that lowering blood levels of nicotinic acid riboside (NAR), one of the non-classical niacin, dramatically increases the therapeutic effect of NAMPTi on NEC. Metabolic studies showed that dietary nicotinic acid is converted to NAR and then released into the circulation, and NAD synthesis using NAR substrates can compensate for the effects of NAMPTi in tumor cells. These findings reveal that niacin restriction with NAMPTi is synthetic lethal to NECs.