Imaging the master regulator of the antioxidant response in non-small cell lung cancer with positron emission tomography.

Autor: Greenwood HE; School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, SE1 7EH, UK., Edwards RS; School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, SE1 7EH, UK., Tyrrell WE; School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, SE1 7EH, UK., Barber AR; School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, SE1 7EH, UK., Baark F; School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, SE1 7EH, UK., Tanc M; School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, SE1 7EH, UK., Khalil E; School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, SE1 7EH, UK., Falzone A; Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Ward NP; Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., DeBlasi JM; Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Torrente L; Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Pearce DR; CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College London, WC1E 6DD, UK.; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, NW1 1AT, UK., Firth G; School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, SE1 7EH, UK., Smith LM; School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, SE1 7EH, UK., Timmermand OV; School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, SE1 7EH, UK., Huebner A; CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College London, WC1E 6DD, UK.; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, NW1 1AT, UK., George ME; School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, SE1 7EH, UK., Swanton C; CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College London, WC1E 6DD, UK.; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, NW1 1AT, UK., Hynds RE; CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College London, WC1E 6DD, UK.; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, NW1 1AT, UK., DeNicola GM; Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Witney TH; School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, SE1 7EH, UK.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2023 Dec 17. Date of Electronic Publication: 2023 Dec 17.
DOI: 10.1101/2023.12.16.572007
Abstrakt: 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. The cystine/glutamate antiporter, system x c - , is one of the >200 cytoprotective proteins controlled by NRF2, which can be non-invasively imaged by ( S )-4-(3- 18 F-fluoropropyl)-l-glutamate ([ 18 F]FSPG) positron emission tomography (PET). Through genetic and pharmacologic manipulation, we show that [ 18 F]FSPG provides a sensitive and specific marker of NRF2 activation in advanced preclinical models of NSCLC. We validate imaging readouts with metabolomic measurements of system x c - activity and their coupling to intracellular glutathione concentration. A redox gene signature was measured in patients from the TRACERx 421 cohort, suggesting an opportunity for patient stratification prior to imaging. Furthermore, we reveal that system x c - is a metabolic vulnerability that can be therapeutically targeted for sustained tumour growth suppression in aggressive NSCLC. Our results establish [ 18 F]FSPG as 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.
Databáze: MEDLINE
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