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

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 and Falzone, Aimee , et al. (2024) In Nature Communications 15(1).
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 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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
keywords
Carcinoma, Non-Small-Cell Lung/diagnostic imaging, Animals, NF-E2-Related Factor 2/metabolism, Humans, Lung Neoplasms/diagnostic imaging, Positron-Emission Tomography/methods, Mice, Cell Line, Tumor, Female, Kelch-Like ECH-Associated Protein 1/metabolism, Fluorine Radioisotopes, Radiopharmaceuticals
in
Nature Communications
volume
15
issue
1
article number
10484
publisher
Nature Publishing Group
external identifiers
  • scopus:85212388828
  • pmid:39690148
ISSN
2041-1723
DOI
10.1038/s41467-024-54852-4
language
English
LU publication?
no
additional info
© 2024. The Author(s).
id
0fe4d0c3-7849-4d10-85e1-6b2096413da6
date added to LUP
2025-01-09 11:58:59
date last changed
2025-06-27 18:49:07
@article{0fe4d0c3-7849-4d10-85e1-6b2096413da6,
  abstract     = {{<p>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.</p>}},
  author       = {{Greenwood, Hannah E and Barber, Abigail R and Edwards, Richard S and Tyrrell, Will E and George, Madeleine E and Dos Santos, Sofia N and Baark, Friedrich and Tanc, Muhammet and Khalil, Eman and Falzone, Aimee and Ward, Nathan P and DeBlasi, Janine M and Torrente, Laura and Soni, Pritin N and Pearce, David R and Firth, George and Smith, Lydia M and Vilhelmsson Timmermand, Oskar and Huebner, Ariana and Swanton, Charles and Hynds, Robert E and DeNicola, Gina M and Witney, Timothy H}},
  issn         = {{2041-1723}},
  keywords     = {{Carcinoma, Non-Small-Cell Lung/diagnostic imaging; Animals; NF-E2-Related Factor 2/metabolism; Humans; Lung Neoplasms/diagnostic imaging; Positron-Emission Tomography/methods; Mice; Cell Line, Tumor; Female; Kelch-Like ECH-Associated Protein 1/metabolism; Fluorine Radioisotopes; Radiopharmaceuticals}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography}},
  url          = {{http://dx.doi.org/10.1038/s41467-024-54852-4}},
  doi          = {{10.1038/s41467-024-54852-4}},
  volume       = {{15}},
  year         = {{2024}},
}