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

• Published in: Nature communications Vol. 15; no. 1; pp. 10484 - 14
• Main Authors: 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, Falzone, Aimee, Ward, Nathan P., DeBlasi, Janine M., Torrente, Laura, Soni, Pritin N., Pearce, David R., Firth, George, Smith, Lydia M., Vilhelmsson Timmermand, Oskar, Huebner, Ariana, Swanton, Charles, Hynds, Robert E., DeNicola, Gina M., Witney, Timothy H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.12.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 14/34; 38/1; 49; 49/39; 59; 59/78; 631/67/1059/153; 631/67/1059/2326; 631/67/1612/1350; 631/67/2321; 631/67/2327; 64/60; 82/1; Animal models; Animals; Carcinoma, Non-Small-Cell Lung - diagnostic imaging; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell activation; Cell Line, Tumor; Female; Fluorine isotopes; Fluorine Radioisotopes; Gene expression; Genetic engineering; Humanities and Social Sciences; Humans; Kelch-Like ECH-Associated Protein 1 - genetics; Kelch-Like ECH-Associated Protein 1 - metabolism; Lung cancer; Lung Neoplasms - diagnostic imaging; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medical imaging; Mice; multidisciplinary; Mutation; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Non-small cell lung carcinoma; NRF2 protein; Pharmacology; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; Radioactive tracers; Radiopharmaceuticals; Science; Science (multidisciplinary); Small cell lung carcinoma; Tomography
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-54852-4

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 x c − radiotracer, [ 18 F]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 [ 18 F]FSPG imaging. Furthermore, we reveal that system x c − is a metabolic vulnerability that can be therapeutically targeted with an antibody-drug conjugate for sustained tumour growth suppression. Overall, our results establish [ 18 F]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. Mutations in the NRF2-KEAP1 pathway is found to be related with therapeutic resistance and poor outcomes of non-small cell lung cancer (NSCLC). Here this group reports that cystine/glutamate antiporter system xc−, controlled by NRF2, can be non-invasively imaged by positron emission tomography thereby providing a sensitive and specific marker of NRF2 activation in advanced preclinical models of NSCLC.