Imaging the master regulator of the antioxidant response in non-small cell lung cancer with positron emission tomography.
Hannah E GreenwoodRichard S EdwardsWill E TyrrellAbigail R BarberFriedrich BaarkMuhammet TancEman KhalilAimee FalzoneNathan P WardJanine M DeBlasiLaura TorrenteDavid R PearceGeorge FirthLydia M SmithOskar Vilhelmsson TimmermandAriana HuebnerMadeleine E GeorgeCharles SwantonRobert E HyndsGina M DeNicolaTimothy H WitneyPublished in: bioRxiv : the preprint server for biology (2023)
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)-ʟ-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.
Keyphrases
- positron emission tomography
- computed tomography
- small cell lung cancer
- high resolution
- oxidative stress
- advanced non small cell lung cancer
- pet imaging
- pet ct
- genome wide
- end stage renal disease
- stem cells
- small molecule
- metabolic syndrome
- bone marrow
- transcription factor
- peritoneal dialysis
- patient reported outcomes
- room temperature
- photodynamic therapy
- adipose tissue
- reactive oxygen species