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Imaging the master regulator of the antioxidant response in non-small cell lung cancer with positron emission tomography

Greenwood, Hannah E ; Edwards, Richard S ; Tyrrell, Will E ; Barber, Abigail R ; Baark, Friedrich ; Tanc, Muhammet ; Khalil, Eman ; Falzone, Aimee ; Ward, Nathan P and DeBlasi, Janine M , et al. (2023) In bioRxiv : the preprint server for biology
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. The cystine/glutamate antiporter, system xc-, is one of the >200 cytoprotective proteins controlled by NRF2, which can be non-invasively imaged by (S)-4-(3-18F-fluoropropyl)-l-glutamate ([18F]FSPG) positron emission tomography (PET). Through genetic and pharmacologic manipulation, we show that [18F]FSPG provides a sensitive and specific marker of NRF2 activation in advanced preclinical models of NSCLC. We validate imaging readouts with metabolomic measurements of system xc- activity and their coupling to intracellular glutathione concentration. A redox gene signature was... (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. The cystine/glutamate antiporter, system xc-, is one of the >200 cytoprotective proteins controlled by NRF2, which can be non-invasively imaged by (S)-4-(3-18F-fluoropropyl)-l-glutamate ([18F]FSPG) positron emission tomography (PET). Through genetic and pharmacologic manipulation, we show that [18F]FSPG provides a sensitive and specific marker of NRF2 activation in advanced preclinical models of NSCLC. We validate imaging readouts with metabolomic measurements of system xc- activity and their coupling to intracellular glutathione concentration. A redox gene signature was measured in patients from the TRACERx 421 cohort, suggesting an opportunity for patient stratification prior to imaging. Furthermore, we reveal that system xc- is a metabolic vulnerability that can be therapeutically targeted for sustained tumour growth suppression in aggressive NSCLC. Our results establish [18F]FSPG as 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
Working paper/Preprint
publication status
published
subject
in
bioRxiv : the preprint server for biology
pages
37 pages
external identifiers
  • pmid:38168428
ISSN
2692-8205
DOI
10.1101/2023.12.16.572007
language
English
LU publication?
no
id
a054d637-f731-4c8a-add0-4ccc8af0f940
date added to LUP
2024-09-26 15:57:38
date last changed
2024-09-26 16:15:35
@misc{a054d637-f731-4c8a-add0-4ccc8af0f940,
  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. The cystine/glutamate antiporter, system xc-, is one of the &gt;200 cytoprotective proteins controlled by NRF2, which can be non-invasively imaged by (S)-4-(3-18F-fluoropropyl)-l-glutamate ([18F]FSPG) positron emission tomography (PET). Through genetic and pharmacologic manipulation, we show that [18F]FSPG provides a sensitive and specific marker of NRF2 activation in advanced preclinical models of NSCLC. We validate imaging readouts with metabolomic measurements of system xc- activity and their coupling to intracellular glutathione concentration. A redox gene signature was measured in patients from the TRACERx 421 cohort, suggesting an opportunity for patient stratification prior to imaging. Furthermore, we reveal that system xc- is a metabolic vulnerability that can be therapeutically targeted for sustained tumour growth suppression in aggressive NSCLC. Our results establish [18F]FSPG as 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 Edwards, Richard S and Tyrrell, Will E and Barber, Abigail R and Baark, Friedrich and Tanc, Muhammet and Khalil, Eman and Falzone, Aimee and Ward, Nathan P and DeBlasi, Janine M and Torrente, Laura and Pearce, David R and Firth, George and Smith, Lydia M and Timmermand, Oskar Vilhelmsson and Huebner, Ariana and George, Madeleine E and Swanton, Charles and Hynds, Robert E and DeNicola, Gina M and Witney, Timothy H}},
  issn         = {{2692-8205}},
  language     = {{eng}},
  month        = {{12}},
  note         = {{Preprint}},
  series       = {{bioRxiv : the preprint server for biology}},
  title        = {{Imaging the master regulator of the antioxidant response in non-small cell lung cancer with positron emission tomography}},
  url          = {{http://dx.doi.org/10.1101/2023.12.16.572007}},
  doi          = {{10.1101/2023.12.16.572007}},
  year         = {{2023}},
}