NNMT-driven metabolic reprogramming creates a NAMPT druggable vulnerability and reveals liquid biopsy biomarkers for TKI resistance in EGFR-mutant NSCLC

IF 10.1 1区 医学 Q1 ONCOLOGY
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.
nnmt驱动的代谢重编程创建了NAMPT可药物易感性,并揭示了egfr突变型NSCLC中TKI耐药的液体活检生物标志物。
肺癌是世界上最致命的肿瘤。尽管针对非小细胞肺癌(NSCLC)中egfr驱动肿瘤的靶向治疗如酪氨酸激酶抑制剂(TKIs)的可用性,但耐药性仍然是显着降低预期寿命的主要因素。在这里,我们确定了tki耐药癌细胞中烟酰胺n -甲基转移酶(NNMT)的表达增加如何转移烟酰胺合成1-甲基烟酰胺(1-MNA),降低NAD+水平,从而产生可药物化的烟酰胺磷酸核糖基转移酶(NAMPT)代谢易感性。我们还报道了NNMT活性的副产物1-MNA的高血液水平与EGFR tki治疗的非小细胞肺癌患者的低生存率显著相关。综上所述,我们的研究结果描述了一种新的、高度特异性的间充质样肿瘤的非遗传代谢合成致死率,揭示了NAMPT作为体内可药物靶点,并建立了1-MNA作为预测和监测NSCLC中EGFR TKI耐药性的新型液体活检生物标志物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
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.
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