Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma

Author:

Nomura Miyuki,Ohuchi Mai,Sakamoto Yoshimi,Kudo Kei,Yaku Keisuke,Soga TomoyoshiORCID,Sugiura Yuki,Morita Mami,Hayashi Kayoko,Miyahara ShukoORCID,Sato Taku,Yamashita Yoji,Ito Shigemi,Kikuchi Naohiko,Sato Ikuro,Saito Rintaro,Yaegashi Nobuo,Fukuhara TatsuroORCID,Yamada Hidekazu,Shima Hiroshi,Nakayama Keiichi I.ORCID,Hirao Atsushi,Kawasaki Kenta,Arai Yoichi,Akamatsu Shusuke,Tanuma Sei-ichi,Sato ToshiroORCID,Nakagawa TakashiORCID,Tanuma NobuhiroORCID

Abstract

AbstractNicotinamide phosphoribosyltransferase (NAMPT) plays a major role in NAD biosynthesis in many cancers and is an attractive potential cancer target. However, factors dictating therapeutic efficacy of NAMPT inhibitors (NAMPTi) are unclear. We report that neuroendocrine phenotypes predict lung and prostate carcinoma vulnerability to NAMPTi, and that NAMPTi therapy against those cancers is enhanced by dietary modification. Neuroendocrine differentiation of tumor cells is associated with down-regulation of genes relevant to quinolinate phosphoribosyltransferase-dependent de novo NAD synthesis, promoting NAMPTi susceptibility in vitro. We also report that circulating nicotinic acid riboside (NAR), a non-canonical niacin absent in culture media, antagonizes NAMPTi efficacy as it fuels NAMPT-independent but nicotinamide riboside kinase 1-dependent NAD synthesis in tumors. In mouse transplantation models, depleting blood NAR by nutritional or genetic manipulations is synthetic lethal to tumors when combined with NAMPTi. Our findings provide a rationale for simultaneous targeting of NAR metabolism and NAMPT therapeutically in neuroendocrine carcinoma.

Funder

MEXT | Japan Society for the Promotion of Science

Japan Agency for Medical Research and Development

Princess Takamatsu Cancer Research Fund

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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