2. Academic Validation
  3. Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma

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

  • Nat Commun. 2023 Dec 13;14(1):8095. doi: 10.1038/s41467-023-43630-3.
Miyuki Nomura 1,  Mai Ohuchi 1,  Yoshimi Sakamoto 1,  Kei Kudo 1 2 3,  Keisuke Yaku 4,  Tomoyoshi Soga 5,  Yuki Sugiura 6,  Mami Morita 1,  Kayoko Hayashi 1,  Shuko Miyahara 1 2 3,  Taku Sato 1,  Yoji Yamashita 1,  Shigemi Ito 1,  Naohiko Kikuchi 1,  Ikuro Sato 7,  Rintaro Saito 5,  Nobuo Yaegashi 3,  Tatsuro Fukuhara 8,  Hidekazu Yamada 1,  Hiroshi Shima 1,  Keiichi I Nakayama 9 10,  Atsushi Hirao 11,  Kenta Kawasaki 12,  Yoichi Arai 13,  Shusuke Akamatsu 14 15,  Sei-Ichi Tanuma 16 17,  Toshiro Sato 12 18,  Takashi Nakagawa 4,  Nobuhiro Tanuma 19 20
Affiliations

Affiliations

  • 1 Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, Japan.
  • 2 Department of Biochemical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan.
  • 3 Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Japan.
  • 4 Department of Molecular and Medical Pharmacology, Faculty of Medicine, University of Toyama, Toyama, Japan.
  • 5 Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan.
  • 6 Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 7 Department of Pathology, Miyagi Cancer Center Hospital, Natori, Japan.
  • 8 Department of Respiratory Medicine, Miyagi Cancer Center Hospital, Natori, Japan.
  • 9 Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyusyu University, Fukuoka, Japan.
  • 10 TMDU Advanced Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
  • 11 Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute and WPI Nano Life Science Institute, Kanazawa University, Kanazawa, Japan.
  • 12 Department of Organoid Medicine, Keio University School of Medicine, Tokyo, Japan.
  • 13 Department of Urology, Miyagi Cancer Center Hospital, Natori, Japan.
  • 14 Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 15 Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • 16 Meikai University Research Institute of Odontology, Sakado, Japan.
  • 17 University of Human Arts and Sciences, Saitama, Japan.
  • 18 Department of Integrated Medicine and Biochemistry, Keio University School of Medicine, Tokyo, Japan.
  • 19 Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, Japan. ntanuma@med.tohoku.ac.jp.
  • 20 Department of Biochemical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan. ntanuma@med.tohoku.ac.jp.
PMID: 38092728 DOI: 10.1038/s41467-023-43630-3
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.

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