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Peer-reviewedCC BY 4.0Molecular Oncology

NAPRT loss promotes lung tumor initiation and growth through AKT signaling independently of NAD + biosynthesis

  • Myung Joon Oh1,2
  • Ji Yun Jang3
  • Yoon Jeon3
  • Gi‐Cheon Kim4
  • Hwanho Lee2
  • Jooyoung Lee5
  • Ju‐Hwa Kim6
  • Hakhyun Kim2
  • Minjee Kim2
  • Ho‐Keun Kwon2,4
  • Ho Lee3,7
  • Hyun Seok Kim1,2
7 affiliations
  1. 1Department of Biomedical Sciences Yonsei University College of Medicine Seoul Korea
  2. 2Graduate School of Medical Science, Brain Korea 21 Project Yonsei University College of Medicine Seoul Korea
  3. 3Division of Cancer Biology, Research Institute National Cancer Center Goyang Korea
  4. 4Department of Microbiology and Immunology Yonsei University College of Medicine Seoul Korea
  5. 5Checkmate Therapeutics Inc. Seoul Korea
  6. 6Graduate Program for Nanomedical Science Yonsei University Seoul Korea
  7. 7Department of Cancer Biomedical Science National Cancer Center Graduate School of Cancer Science and Policy Goyang Korea
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Abstract

Nicotinamide adenine dinucleotide (NAD+) metabolism is frequently rewired in cancer, creating metabolic vulnerabilities that can be therapeutically exploited. Loss of nicotinate phosphoribosyltransferase (NAPRT), a rate‐limiting enzyme of the Preiss–Handler pathway, renders tumor cells dependent on nicotinamide phosphoribosyltransferase (NAMPT)‐mediated NAD+ synthesis and serves as a predictive biomarker for NAMPT inhibitor sensitivity. However, whether NAPRT loss actively contributes to tumorigenesis remains unclear. Here, we show that NAPRT depletion promotes tumorigenic phenotypes in lung cancer through a noncanonical mechanism independent of NAD+ biosynthesis. NAPRT knockdown enhanced clonogenic initiation, sphere formation, and invasive capacity. Mechanistically, NAPRT loss drives mTORC2‐dependent activation of the AKT signaling axis. This effect was not reversed by nicotinic acid or NAD+ supplementation or recapitulated by catalytic inhibition of NAPRT, indicating a function distinct from its metabolic role. Pharmacologic AKT inhibition attenuated the enhanced growth induced by NAPRT depletion. In vivo, lung‐specific Naprt deletion significantly increased tumor burden in Kras G12D‐driven mice without altering tumor histology or immune cell composition. Together, these findings identify a previously unrecognized tumor‐suppressive role for NAPRT in lung tumor initiation and growth.

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Cite

BibTeXRIS
BibTeX
@article{oh2026naprt,
  title = {{NAPRT loss promotes lung tumor initiation and growth through AKT signaling independently of NAD + biosynthesis}},
  author = {Myung Joon Oh and Ji Yun Jang and Yoon Jeon and Gi‐Cheon Kim and Hwanho Lee and Jooyoung Lee and Ju‐Hwa Kim and Hakhyun Kim and Minjee Kim and Ho‐Keun Kwon and Ho Lee and Hyun Seok Kim},
  journal = {Molecular Oncology},
  year = {2026},
  month = sep,
  doi = {10.1002/1878-0261.70330},
  url = {https://doi.org/10.1002/1878-0261.70330},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - NAPRT loss promotes lung tumor initiation and growth through AKT signaling independently of NAD + biosynthesis
AU  - Myung Joon Oh
AU  - Ji Yun Jang
AU  - Yoon Jeon
AU  - Gi‐Cheon Kim
AU  - Hwanho Lee
AU  - Jooyoung Lee
AU  - Ju‐Hwa Kim
AU  - Hakhyun Kim
AU  - Minjee Kim
AU  - Ho‐Keun Kwon
AU  - Ho Lee
AU  - Hyun Seok Kim
PY  - 2026
DA  - 2026/09/25
JO  - Molecular Oncology
DO  - 10.1002/1878-0261.70330
UR  - https://doi.org/10.1002/1878-0261.70330
AB  - Nicotinamide adenine dinucleotide (NAD+) metabolism is frequently rewired in cancer, creating metabolic vulnerabilities that can be therapeutically exploited. Loss of nicotinate phosphoribosyltransferase (NAPRT), a rate‐limiting enzyme of the Preiss–Handler pathway, renders tumor cells dependent on nicotinamide phosphoribosyltransferase (NAMPT)‐mediated NAD+ synthesis and serves as a predictive biomarker for NAMPT inhibitor sensitivity. However, whether NAPRT loss actively contributes to tumorigenesis remains unclear. Here, we show that NAPRT depletion promotes tumorigenic phenotypes in lung cancer through a noncanonical mechanism independent of NAD+ biosynthesis. NAPRT knockdown enhanced clonogenic initiation, sphere formation, and invasive capacity. Mechanistically, NAPRT loss drives mTORC2‐dependent activation of the AKT signaling axis. This effect was not reversed by nicotinic acid or NAD+ supplementation or recapitulated by catalytic inhibition of NAPRT, indicating a function distinct from its metabolic role. Pharmacologic AKT inhibition attenuated the enhanced growth induced by NAPRT depletion. In vivo, lung‐specific Naprt deletion significantly increased tumor burden in Kras G12D‐driven mice without altering tumor histology or immune cell composition. Together, these findings identify a previously unrecognized tumor‐suppressive role for NAPRT in lung tumor initiation and growth.
SN  - 1574-7891
SN  - 1878-0261
ER  -