Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography
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 t...
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| Language: | English |
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54852-4 |
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| author | 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 Swanton Robert E. Hynds Gina M. DeNicola Timothy H. Witney |
| author_facet | 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 Swanton Robert E. Hynds Gina M. DeNicola Timothy H. Witney |
| author_sort | Hannah E. Greenwood |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-3dcf089945564aceb0bdbed94a00b1bb |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-3dcf089945564aceb0bdbed94a00b1bb2024-12-22T12:36:13ZengNature PortfolioNature Communications2041-17232024-12-0115111410.1038/s41467-024-54852-4Imaging NRF2 activation in non-small cell lung cancer with positron emission tomographyHannah E. Greenwood0Abigail R. Barber1Richard S. Edwards2Will E. Tyrrell3Madeleine E. George4Sofia N. dos Santos5Friedrich Baark6Muhammet Tanc7Eman Khalil8Aimee Falzone9Nathan P. Ward10Janine M. DeBlasi11Laura Torrente12Pritin N. Soni13David R. Pearce14George Firth15Lydia M. Smith16Oskar Vilhelmsson Timmermand17Ariana Huebner18Charles Swanton19Robert E. Hynds20Gina M. DeNicola21Timothy H. Witney22School of Biomedical Engineering & Imaging Sciences, King’s College London, St Thomas’ HospitalSchool of Biomedical Engineering & Imaging Sciences, King’s College London, St Thomas’ HospitalSchool of Biomedical Engineering & Imaging Sciences, King’s College London, St Thomas’ HospitalSchool of Biomedical Engineering & Imaging Sciences, King’s College London, St Thomas’ HospitalSchool of Biomedical Engineering & Imaging Sciences, King’s College London, St Thomas’ HospitalSchool of Biomedical Engineering & Imaging Sciences, King’s College London, St Thomas’ HospitalSchool of Biomedical Engineering & Imaging Sciences, King’s College London, St Thomas’ HospitalSchool of Biomedical Engineering & Imaging Sciences, King’s College London, St Thomas’ HospitalSchool of Biomedical Engineering & Imaging Sciences, King’s College London, St Thomas’ HospitalDepartment of Metabolism and Physiology, H. Lee Moffitt Cancer CenterDepartment of Metabolism and Physiology, H. Lee Moffitt Cancer CenterDepartment of Metabolism and Physiology, H. Lee Moffitt Cancer CenterDepartment of Metabolism and Physiology, H. Lee Moffitt Cancer CenterDepartment of Metabolism and Physiology, H. Lee Moffitt Cancer CenterCRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College LondonSchool of Biomedical Engineering & Imaging Sciences, King’s College London, St Thomas’ HospitalSchool of Biomedical Engineering & Imaging Sciences, King’s College London, St Thomas’ HospitalSchool of Biomedical Engineering & Imaging Sciences, King’s College London, St Thomas’ HospitalCRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College LondonCRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College LondonCRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College LondonDepartment of Metabolism and Physiology, H. Lee Moffitt Cancer CenterSchool of Biomedical Engineering & Imaging Sciences, King’s College London, St Thomas’ HospitalAbstract 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.https://doi.org/10.1038/s41467-024-54852-4 |
| spellingShingle | 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 Swanton Robert E. Hynds Gina M. DeNicola Timothy H. Witney Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography Nature Communications |
| title | Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography |
| title_full | Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography |
| title_fullStr | Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography |
| title_full_unstemmed | Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography |
| title_short | Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography |
| title_sort | imaging nrf2 activation in non small cell lung cancer with positron emission tomography |
| url | https://doi.org/10.1038/s41467-024-54852-4 |
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