Hannah E. Greenwood et al, Nature Communications, 2024
Summary
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, positron emission tomography imaging with the system xc- radiotracer, [18F]FSPG is shown to provide a sensitive and specific marker of NRF2 activation in orthotopic, patient-derived, and genetically engineered mouse models of NSCLC. NRF2-related gene expression signature was found in a large cohort of NSCLC patients, suggesting an opportunity to preselect patients prior to [18F]FSPG imaging. Furthermore, it was revealed that system xc- is a metabolic vulnerability that can be therapeutically targeted with an antibody-drug conjugate for sustained tumour growth suppression. Overall, these 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.
Results from nanoScan® PET/CT
In NSCLC, NRF2 activation results in resistance across the spectrum of currently available therapeutics. A non-invasive measure of NRF2 activation may therefore provide an attractive solution for the prediction of therapy resistance in NSCLC, which may further reveal cancer-specific vulnerabilities for the precision treatment of refractive disease.
Fig. 3 | [18F]FSPG PET can differentiate NRF2-high from NRF2-low tumours when grown orthotopically in the lungs of mice. b Representative in vivo [18F]FSPG PET/CT maximum intensity projections (MIPs; top) and axial single-slice PET/CT (bottom) of mice bearing H1299 or H460 orthotopic lung tumours. Dashed lines represent the tumour outline. P pancreas, K kidney, B bladder. d Representative western blot for xCT and NRF2 expression in H1299 and H460 orthotopically grown tumours.
Fig. 4 | [18F]FSPG retention is increased in NRF2 mutant mice. d Representative coronal [18F]FSPG PET/CT images of 40–60 min summed activity in KP and KPN tumour-bearing mice. Dashed white lines indicate the lung. B bladder, P pancreas.
Fig. 5 | An antioxidant gene signature accompanies NRF2 mutations in patient tumours and patient derived xenograft (PDX) models, which is detectable by [18F]FSPG PET. b Representative [18F]FSPG MIP of mice bearing PDXs either with (CRUK0772 R1) or without (CRUK0640 R8) a NRF2 mutation.
PET/CT imaging: mice received a single bolus i.v. injection through a tail vein cannula of ∼3 MBq [18F]FSPG in 100 µL PBS. 40 min p.i., static PET imaging scans were acquired for 20 min on a Mediso NanoScan PET/CT system. CT images were acquired for anatomical visualisation and attenuation correction. Individual tumour volumes of interest were constructed by manually drawing sequential 2D regions of interest (ROI) on the CT images. The percentage of tumour tissue was determined.
∑ [18F]FSPG retention increased in tumours with NRF2 activation compared to those with a normal-functioning NRF2/KEAP1 axis. [18F]FSPG imaging could be made available to patients at most major hospitals which currently use [18F]FDG for tumour staging/restaging.
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