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Article 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 x, is one of the >200 cytoprotective proteins controlled by NRF2, which can be non-invasively imaged by ()-4-(3-F-fluoropropyl)-l-glutamate ([F]FSPG) positron emission tomography (PET). Through genetic and pharmacologic manipulation, we show that [F]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 x 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 x is a metabolic vulnerability that can be therapeutically targeted for sustained tumour growth suppression in aggressive NSCLC. Our results establish [F]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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10760199 | PMC |
| http://dx.doi.org/10.1101/2023.12.16.572007 | DOI Listing |
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