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

被引：7

作者：

Greenwood, Hannah E. ^{[1
]}

Barber, Abigail R. ^{[1
]}

Edwards, Richard S. ^{[1
]}

Tyrrell, Will E. ^{[1
]}

George, Madeleine E. ^{[1
]}

dos Santos, Sofia N. ^{[1
]}

Baark, Friedrich ^{[1
]}

Tanc, Muhammet ^{[1
]}

Khalil, Eman ^{[1
]}

Falzone, Aimee ^{[2
]}

Ward, Nathan P. ^{[2
]}

Deblasi, Janine M. ^{[2
]}

Torrente, Laura ^{[2
]}

Soni, Pritin N. ^{[2
]}

Pearce, David R. ^{[3
,4
]}

Firth, George ^{[1
]}

Smith, Lydia M. ^{[1
]}

Timmermand, Oskar Vilhelmsson ^{[1
]}

Huebner, Ariana ^{[3
,4
]}

Swanton, Charles ^{[3
,4
]}

Hynds, Robert E. ^{[3
,4
]}

Denicola, Gina M. ^{[2
]}

Witney, Timothy H. ^{[1
]}

机构：

[1] Kings Coll London, St Thomas Hosp, Sch Biomed Engn & Imaging Sci, London, England

[2] H Lee Moffitt Canc Ctr & Res Inst, Dept Metab & Physiol, Tampa, FL USA

[3] UCL, UCL Canc Inst, CRUK Lung Canc Ctr Excellence, London, England

[4] Francis Crick Inst, Canc Evolut & Genome Instabil Lab, London, England

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

基金：

英国惠康基金; 英国科研创新办公室; 英国医学研究理事会;

关键词：

CYSTINE/GLUTAMATE EXCHANGE TRANSPORTER; SYSTEM X(C)(-); RESISTANCE; PET; OPPORTUNITIES; METABOLISM; MECHANISMS; EXPRESSION; EVOLUTION; GLUTAMINE;

D O I：

10.1038/s41467-024-54852-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 xc- radiotracer, [18F]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 [18F]FSPG imaging. Furthermore, we reveal that system xc- is a metabolic vulnerability that can be therapeutically targeted with an antibody-drug conjugate for sustained tumour growth suppression. Overall, our results establish [18F]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.

引用

页数：14

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