| First Author | Greenwood HE | Year | 2024 |
| Journal | Nat Commun | Volume | 15 |
| Issue | 1 | Pages | 10484 |
| PubMed ID | 39690148 | Mgi Jnum | J:359776 |
| Mgi Id | MGI:7789795 | Doi | 10.1038/s41467-024-54852-4 |
| Citation | Greenwood HE, et al. (2024) Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography. Nat Commun 15(1):10484 |
| abstractText | 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. |
