NNMT-driven metabolic reprogramming creates a NAMPT druggable vulnerability and reveals liquid biopsy biomarkers for TKI resistance in EGFR-mutant NSCLC
Lung cancer is the deadliest neoplasia worldwide. Despite the availability of targeted therapies like tyrosine kinase inhibitors (TKIs) for EGFR-driven tumours in Non-Small Cell Lung Cancer (NSCLC), drug resistance remains a major factor that dramatically cuts life expectancy. Here we identify how increased expression of nicotinamide N-methyltransferase (NNMT) in TKI-resistant cancer cells diverts nicotinamide to synthesise 1-Methylnicotinamide (1-MNA) and lowers NAD<sup>+</sup> levels that generates a druggable nicotinamide phosphoribosyltransferase (NAMPT) metabolic vulnerability. We also report that high blood levels of 1-MNA, the by-product of NNMT activity, are significantly associated with lower survival rates in EGFR TKI-treated NSCLC patients. Taken together, our findings describe a new and highly specific non-genetic metabolic synthetic lethality for mesenchymal-like tumours, which exposes NAMPT as an in vivo druggable target and establishes 1-MNA as a novel liquid biopsy biomarker to predict and monitor EGFR TKI resistance in NSCLC.
Authors
- Óscar Juan (ORCID: https://orcid.org/0000-0002-7772-9030)
- Takeshi Shimamura (ORCID: https://orcid.org/0000-0002-5402-7204)
- Santiago Álvarez Montero (ORCID: https://orcid.org/0000-0002-8282-8877)
- Cristina Carreres-Rey
- Paloma Martín-Martorell (ORCID: https://orcid.org/0000-0002-6728-8366)
- José M. Galbis (ORCID: https://orcid.org/0000-0002-1058-0171)
- Eva Tamayo-Torres
- Amelia Insa (ORCID: https://orcid.org/0000-0002-3438-6170)
- J. Alcácer
- Silvia Calabuig‐Fariñas (ORCID: https://orcid.org/0000-0001-7749-174X)
- Inés Pulido (ORCID: https://orcid.org/0000-0002-1637-6702)
- Javier Pereda (ORCID: https://orcid.org/0000-0002-8690-8938)
- Javier Alcácer Fernández-Coronado
- Marta-Leonor Rodríguez
- Juan Carlos García‐Cañaveras (ORCID: https://orcid.org/0000-0001-7112-1537)
- Eloísa Jantus‐Lewintre (ORCID: https://orcid.org/0000-0001-7395-4380)
- Lourdes Chuliá‐Peris (ORCID: https://orcid.org/0000-0002-0355-8187)
- Salvador Mena (ORCID: https://orcid.org/0000-0002-6423-4741)
- Antonio Cremades (ORCID: https://orcid.org/0000-0002-6522-932X)
- Miguel Aupí (ORCID: https://orcid.org/0000-0002-2252-5102)
- Marta Benet (ORCID: https://orcid.org/0000-0002-7910-4755)
- Julián Carretero (ORCID: https://orcid.org/0000-0001-7269-8506)
- Juan Sandoval (ORCID: https://orcid.org/0000-0002-5100-973X)
- Agustín Lahoz (ORCID: https://orcid.org/0000-0001-7232-0626)
- Salvador Aparisi
- Malek G. Massad
- J.H.R. Becker
Institutions
- Universitat de València (ES)
- University of Illinois Chicago (US)
- Hospital de La Ribera (ES)
- Hospital Clínico Universitario de Valencia (ES)
- Essex Cardiothoracic Centre (GB)
- Hospital Quirónsalud Barcelona (ES)
- University of Illinois Hospital & Health Sciences System (US)
- Fundación General (ES)
- INCLIVA Health Research Institute (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Instituto de Investigación Sanitaria La Fe (ES)
- Universitat Politècnica de València (ES)
Publication Details
- Journal
- Cancer Letters
- Published
- 2025-09-09
- DOI
- https://doi.org/10.1016/j.canlet.2025.218032
- Primary Topic
- PI3K/AKT/mTOR signaling in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ministerio de Ciencia, Innovación y Universidades
- Generalitat Valenciana
- INCLIVA Instituto de Investigación Sanitaria
- National Institutes of Health
- University of Illinois at Urbana-Champaign
- Instituto de Salud Carlos III
- European Regional Development Fund
- Congressionally Directed Medical Research Programs