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

Hannah E Greenwood, Abigail R Barber, Richard S Edwards, Will E Tyrrell, Madeleine E George, Sofia N Dos Santos, Friedrich Baark, Muhammet Tanc, Eman Khalil, Aimee Falzone, Nathan P Ward, Janine M DeBlasi, Laura Torrente, Pritin N Soni, David R Pearce, George Firth, Lydia M Smith, Oskar Vilhelmsson Timmermand, Ariana Huebner, Charles SwantonRobert E Hynds, Gina M DeNicola, Timothy H Witney

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

Sammanfattning

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.

Originalspråkengelska
Artikelnummer10484
TidskriftNature Communications
Volym15
Nummer1
DOI
StatusPublished - 2024 dec. 17
Externt publiceradJa

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© 2024. The Author(s).

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