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Imaging the master regulator of the antioxidant response 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. 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-(3-¹⁸F-fluoropropyl)-l-glutamate ([¹⁸F]FSPG) positron emission tomography (PET). Through genetic and pharmacologic manipulation, we show that [¹⁸F]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 [¹⁸F]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.

SUBMITTER: Greenwood HE

PROVIDER: S-EPMC10760199 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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

Greenwood Hannah E HE Edwards Richard S RS Tyrrell Will E WE Barber Abigail R AR Baark Friedrich F Tanc Muhammet M Khalil Eman E Falzone Aimee A Ward Nathan P NP DeBlasi Janine M JM Torrente Laura L Pearce David R DR Firth George G Smith Lydia M LM Timmermand Oskar Vilhelmsson OV Huebner Ariana A George Madeleine E ME Swanton Charles C Hynds Robert E RE DeNicola Gina M GM Witney Timothy H TH

bioRxiv : the preprint server for biology 20231217

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 xc-, is one of the >200 cytoprotective proteins controlled by NRF2, which can be non-invasively imaged by (S)-4-(3-18F-fluoropropyl)-l-glutamate ([18F]FSPG) positron emission tomography (PET). Through genetic and pharmacologic manipulation, we sho ...[more]

PMID: 38168428

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Project description:BackgroundThe chemotherapy resistance of non-small cell lung cancer (NSCLC) remains a clinic challenge and is closely associated with several biomarkers including epidermal growth factor receptor (EGFR) ( Drugs 72(Suppl 1):28-36, 012.), p53 ( Med Sci Monit 11(6):HY11-HY20, 2005.) and excision repair cross complementing gene 1 (ERCC1) ( J Thorac Oncol 8(5):582-586, 2013.). Fluorodeoxyglucose positron emission tomography (FDG-PET) is the best non-invasive surrogate for tumor biology with the maximal standardized uptake values (SUVmax) being the most important paradigm. However, there are limited data correlating FDG-PET with the chemotherapy resistant tumor markers. The purpose of this study was to determine the correlation of chemotherapy related tumor marker expression with FDG-PET SUVmax in NSCLC.MethodsFDG-PET SUVmax was calculated in chemotherapy naïve patients with NSCLC (n=62) and immunohistochemical analysis was performed for EGFR, p53 or ERCC1 on the intraoperative NSCLC tissues. Each tumor marker was assessed independently by two pathologists using common grading criteria. The SUVmax difference based on the histologic characteristics, gender, differentiation, grading and age as well as correlation analysis among these parameters were performed. Multiple stepwise regression analysis was further performed to determine the primary predictor for SUVmax and the receiver operating characteristics (ROC) curve analysis was performed to detect the optimized sensitivity and specificity for SUVmax in suggesting chemotherapy resistant tumor markers.ResultsThe significant tumor type (P=0.045), differentiation (P=0.021), p53 (P=0.000) or ERCC1 (P=0.033) positivity dependent differences of SUVmax values were observed. The tumor differentiation is significantly correlated with SUVmax (R=-0.327), tumor size (R=-0.286), grading (R=-0.499), gender (R=0.286) as well as the expression levels for p53 (R= -0.605) and ERCC1 (R=-0.644). The expression level of p53 is significantly correlated with SUVmax (R=0.508) and grading (R=0.321). Furthermore, multiple stepwise regression analysis revealed that p53 expression was the primary predictor for SUVmax. When the cut-off value of SUVmax was set at 5.15 in the ROC curve analysis, the sensitivity and specificity of SUVmax in suggesting p53 positive NSCLC were 79.5% and 47.8%, respectively.ConclusionThe current study suggests that SUVmax of primary tumor on FDG-PET might be a simple and good non-invasive method for predicting p53-related chemotherapy resistance in NSCLC when we set the cu-off value of SUVmax at 5.15.

Dataset Information

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

Publications

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

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