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

Miyuki Nomura, Mai Ohuchi, Yoshimi Sakamoto, Kei Kudo, Keisuke Yaku, Tomoyoshi Soga, Yuki Sugiura, Mami Morita, Kayoko Hayashi, Shuko Miyahara, Taku Sato, Yoji Yamashita, Shigemi Ito, Naohiko Kikuchi, Ikuro Sato, Rintaro Saito, Nobuo Yaegashi, Tatsuro Fukuhara, Hidekazu Yamada, Hiroshi Shima, Keiichi I. Nakayama, Atsushi Hirao, Kenta Kawasaki, Yoichi Arai, Shusuke Akamatsu, Sei-ichi Tanuma, Toshiro Sato, Takashi Nakagawa and Nobuhiro Tanuma ()
Additional contact information
Miyuki Nomura: Miyagi Cancer Center Research Institute
Mai Ohuchi: Miyagi Cancer Center Research Institute
Yoshimi Sakamoto: Miyagi Cancer Center Research Institute
Kei Kudo: Miyagi Cancer Center Research Institute
Keisuke Yaku: University of Toyama
Tomoyoshi Soga: Keio University
Yuki Sugiura: Kyoto University Graduate School of Medicine
Mami Morita: Miyagi Cancer Center Research Institute
Kayoko Hayashi: Miyagi Cancer Center Research Institute
Shuko Miyahara: Miyagi Cancer Center Research Institute
Taku Sato: Miyagi Cancer Center Research Institute
Yoji Yamashita: Miyagi Cancer Center Research Institute
Shigemi Ito: Miyagi Cancer Center Research Institute
Naohiko Kikuchi: Miyagi Cancer Center Research Institute
Ikuro Sato: Miyagi Cancer Center Hospital
Rintaro Saito: Keio University
Nobuo Yaegashi: Tohoku University Graduate School of Medicine
Tatsuro Fukuhara: Miyagi Cancer Center Hospital
Hidekazu Yamada: Miyagi Cancer Center Research Institute
Hiroshi Shima: Miyagi Cancer Center Research Institute
Keiichi I. Nakayama: Kyusyu University
Atsushi Hirao: Kanazawa University
Kenta Kawasaki: Keio University School of Medicine
Yoichi Arai: Miyagi Cancer Center Hospital
Shusuke Akamatsu: Kyoto University Graduate School of Medicine
Sei-ichi Tanuma: Meikai University Research Institute of Odontology
Toshiro Sato: Keio University School of Medicine
Takashi Nakagawa: University of Toyama
Nobuhiro Tanuma: Miyagi Cancer Center Research Institute

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Nicotinamide 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.

Date: 2023
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DOI: 10.1038/s41467-023-43630-3

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