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. 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 Swanton, Robert E. Hynds, Gina M. DeNicola and Timothy H. Witney ()
Additional contact information
Hannah E. Greenwood: King’s College London, St Thomas’ Hospital
Abigail R. Barber: King’s College London, St Thomas’ Hospital
Richard S. Edwards: King’s College London, St Thomas’ Hospital
Will E. Tyrrell: King’s College London, St Thomas’ Hospital
Madeleine E. George: King’s College London, St Thomas’ Hospital
Sofia N. Santos: King’s College London, St Thomas’ Hospital
Friedrich Baark: King’s College London, St Thomas’ Hospital
Muhammet Tanc: King’s College London, St Thomas’ Hospital
Eman Khalil: King’s College London, St Thomas’ Hospital
Aimee Falzone: H. Lee Moffitt Cancer Center
Nathan P. Ward: H. Lee Moffitt Cancer Center
Janine M. DeBlasi: H. Lee Moffitt Cancer Center
Laura Torrente: H. Lee Moffitt Cancer Center
Pritin N. Soni: H. Lee Moffitt Cancer Center
David R. Pearce: UCL Cancer Institute, University College London
George Firth: King’s College London, St Thomas’ Hospital
Lydia M. Smith: King’s College London, St Thomas’ Hospital
Oskar Vilhelmsson Timmermand: King’s College London, St Thomas’ Hospital
Ariana Huebner: UCL Cancer Institute, University College London
Charles Swanton: UCL Cancer Institute, University College London
Robert E. Hynds: UCL Cancer Institute, University College London
Gina M. DeNicola: H. Lee Moffitt Cancer Center
Timothy H. Witney: King’s College London, St Thomas’ Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-14

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 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.

Date: 2024
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DOI: 10.1038/s41467-024-54852-4

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