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利用正电子发射断层扫描成像非小细胞肺癌中的NRF2激活情况。

Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography.

作者信息

Greenwood Hannah E, Barber Abigail R, Edwards Richard S, Tyrrell Will E, George Madeleine E, Dos Santos Sofia N, Baark Friedrich, Tanc Muhammet, Khalil Eman, Falzone Aimee, Ward Nathan P, DeBlasi Janine M, Torrente Laura, Soni Pritin N, Pearce David R, Firth George, Smith Lydia M, Vilhelmsson Timmermand Oskar, Huebner Ariana, Swanton Charles, Hynds Robert E, DeNicola Gina M, Witney Timothy H

机构信息

School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, UK.

Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.

出版信息

Nat Commun. 2024 Dec 17;15(1):10484. doi: 10.1038/s41467-024-54852-4.

DOI:10.1038/s41467-024-54852-4
PMID:39690148
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11652680/
Abstract

Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. Currently, there is no means to non-invasively identify NRF2 activation in living subjects. Here, we show that positron emission tomography imaging with the system x radiotracer, [F]FSPG, provides a sensitive and specific marker of NRF2 activation in orthotopic, patient-derived, and genetically engineered mouse models of NSCLC. We found a NRF2-related gene expression signature in a large cohort of NSCLC patients, suggesting an opportunity to preselect patients prior to [F]FSPG imaging. Furthermore, we reveal that system x is a metabolic vulnerability that can be therapeutically targeted with an antibody-drug conjugate for sustained tumour growth suppression. Overall, our results establish [F]FSPG as a predictive marker of therapy resistance in NSCLC and provide the basis for the clinical evaluation of both imaging and therapeutic agents that target this important antioxidant pathway.

摘要

NRF2-KEAP1通路的突变在非小细胞肺癌（NSCLC）中很常见，并导致广谱治疗耐药性，从而导致预后不良。目前，尚无在活体受试者中无创识别NRF2激活的方法。在此，我们表明，使用系统x放射性示踪剂[F]FSPG进行正电子发射断层扫描成像，可在NSCLC的原位、患者来源和基因工程小鼠模型中提供NRF2激活的敏感且特异的标志物。我们在一大群NSCLC患者中发现了与NRF2相关的基因表达特征，这表明有机会在[F]FSPG成像之前预先选择患者。此外，我们揭示系统x是一种代谢脆弱性，可用抗体-药物偶联物进行治疗靶向，以持续抑制肿瘤生长。总体而言，我们的结果确立了[F]FSPG作为NSCLC治疗耐药性的预测标志物，并为针对这一重要抗氧化途径的成像和治疗药物的临床评估提供了依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e67/11652680/839d534529e5/41467_2024_54852_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e67/11652680/52e1cdaf6310/41467_2024_54852_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e67/11652680/04e0c25c037d/41467_2024_54852_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e67/11652680/2d01def5a3a1/41467_2024_54852_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e67/11652680/40560680b0b9/41467_2024_54852_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e67/11652680/27b777bf5741/41467_2024_54852_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e67/11652680/636781e13262/41467_2024_54852_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e67/11652680/839d534529e5/41467_2024_54852_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e67/11652680/52e1cdaf6310/41467_2024_54852_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e67/11652680/04e0c25c037d/41467_2024_54852_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e67/11652680/2d01def5a3a1/41467_2024_54852_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e67/11652680/40560680b0b9/41467_2024_54852_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e67/11652680/27b777bf5741/41467_2024_54852_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e67/11652680/636781e13262/41467_2024_54852_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e67/11652680/839d534529e5/41467_2024_54852_Fig7_HTML.jpg

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