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Published on: July 21, 2018
NNMT-driven metabolic reprogramming creates a NAMPT druggable vulnerability and reveals liquid biopsy biomarkers for
I Pulido1, J C García-Cañaveras2, M L Rodríguez3
1Department of Surgery, Division of Cardiothoracic Surgery, USA; University of Illinois Hospital & Health Sciences System Cancer Center, University of Illinois Chicago, Chicago, IL, 60612, USA; Department of Physiology, Universitat de Valencia, Valencia, Spain.
Abstract:
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+ 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.
Insights
Nicotinamide N-methyltransferase (NNMT) drives resistance to EGFR tyrosine kinase inhibitors (TKIs) in Non-Small Cell Lung Cancer (NSCLC). Targeting NAMPT or using 1-Methylnicotinamide (1-MNA) as a biomarker may overcome TKI resistance.
Area of Science:
- Oncology
- Metabolic pathways
- Cancer drug resistance
Background:
- Non-Small Cell Lung Cancer (NSCLC) is a leading cause of cancer death globally.
- Targeted therapies like EGFR tyrosine kinase inhibitors (TKIs) are effective but limited by drug resistance.
- Drug resistance significantly reduces survival rates in NSCLC patients.
Purpose of the Study:
- To investigate the metabolic mechanisms underlying TKI resistance in EGFR-driven NSCLC.
- To identify novel therapeutic targets and biomarkers for overcoming TKI resistance.
- To explore the role of nicotinamide N-methyltransferase (NNMT) and its by-products in NSCLC progression.
Main Methods:
- Analysis of NNMT expression in TKI-resistant cancer cells.
- Measurement of NAD+ levels and nicotinamide metabolism.
- Quantification of 1-Methylnicotinamide (1-MNA) in patient blood samples.
- Correlation of 1-MNA levels with survival rates in EGFR TKI-treated NSCLC patients.
Main Results:
- Increased NNMT expression in TKI-resistant cells diverts nicotinamide, lowering NAD+ levels.
- This metabolic shift creates a vulnerability in nicotinamide phosphoribosyltransferase (NAMPT) activity.
- High blood levels of 1-MNA, a NNMT by-product, are associated with poorer survival in NSCLC patients treated with EGFR TKIs.
- A non-genetic metabolic synthetic lethality was identified in mesenchymal-like tumors.
Conclusions:
- NNMT-mediated metabolic reprogramming is a key mechanism of EGFR TKI resistance in NSCLC.
- NAMPT represents a druggable target for overcoming TKI resistance.
- 1-MNA serves as a novel liquid biopsy biomarker for predicting and monitoring EGFR TKI resistance in NSCLC.
- These findings offer a new therapeutic strategy and diagnostic tool for NSCLC treatment.
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