NNMT-driven metabolic reprogramming creates a NAMPT druggable vulnerability and reveals liquid biopsy biomarkers for TKI resistance in EGFR-mutant NSCLC
I. Pulido , J.C. García-Cañaveras , M.L. Rodríguez , J.H. Becker , A. López , M. Aupí , S. Aparisi , L. Chuliá-Peris , E. Tamayo-Torres , C. Carreres-Rey , J. Alcácer Fernández-Coronado , M. Benet , S. Montero , S. Mena , J. Sandoval , J. Pereda , J. Alcácer , S. Calabuig-Fariñas , E. Jantus-Lewintre , A. Cremades , J. Carretero
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引用次数: 0
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.
期刊介绍:
Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research.
Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy.
By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.