Imaging the master regulator of the antioxidant response in non-small cell lung cancer with positron emission tomography
(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.
(Less)
- author
- publishing date
- 2023-12-17
- 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 >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}}, }