Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography
Hannah E. Greenwood, Abigail R. Barber, Richard Edwards, Will E. Tyrrell, Madeleine E. George, Sofia Nascimento dos Santos, Friedrich Baark, Muhammet Tanç, 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 Swanton, Robert E. Hynds, Gina M. DeNicola, Timothy H. Witney
Abstract
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. 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.