Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography

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

doi:10.1038/s41467-024-54852-4

Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography

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 SwantonRobert E Hynds, Gina M DeNicola, Timothy H Witney

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	10484
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-54852-4
Publication status	Published - 2024 Dec 17
Externally published	Yes

Bibliographical note

Free keywords

Carcinoma, Non-Small-Cell Lung/diagnostic imaging
Animals
NF-E2-Related Factor 2/metabolism
Humans
Lung Neoplasms/diagnostic imaging
Positron-Emission Tomography/methods
Mice
Cell Line, Tumor
Female
Kelch-Like ECH-Associated Protein 1/metabolism
Fluorine Radioisotopes
Radiopharmaceuticals

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-024-54852-4Licence: CC BY

Cite this

Greenwood, H. E., Barber, A. R., Edwards, R. S., Tyrrell, W. E., George, M. E., Dos Santos, S. N., Baark, F., Tanc, M., Khalil, E., Falzone, A., Ward, N. P., DeBlasi, J. M., Torrente, L., Soni, P. N., Pearce, D. R., Firth, G., Smith, L. M., Vilhelmsson Timmermand, O., Huebner, A., ... Witney, T. H. (2024). Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography. Nature Communications, 15(1), Article 10484. https://doi.org/10.1038/s41467-024-54852-4

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title = "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 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.",

keywords = "Carcinoma, Non-Small-Cell Lung/diagnostic imaging, Animals, NF-E2-Related Factor 2/metabolism, Humans, Lung Neoplasms/diagnostic imaging, Positron-Emission Tomography/methods, Mice, Cell Line, Tumor, Female, Kelch-Like ECH-Associated Protein 1/metabolism, Fluorine Radioisotopes, Radiopharmaceuticals",

author = "Greenwood, {Hannah E} and Barber, {Abigail R} and Edwards, {Richard S} and Tyrrell, {Will E} and George, {Madeleine E} and {Dos Santos}, {Sofia N} and Friedrich Baark and Muhammet Tanc and Eman Khalil and Aimee Falzone and Ward, {Nathan P} and DeBlasi, {Janine M} and Laura Torrente and Soni, {Pritin N} and Pearce, {David R} and George Firth and Smith, {Lydia M} and {Vilhelmsson Timmermand}, Oskar and Ariana Huebner and Charles Swanton and Hynds, {Robert E} and DeNicola, {Gina M} and Witney, {Timothy H}",

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year = "2024",

month = dec,

day = "17",

doi = "10.1038/s41467-024-54852-4",

language = "English",

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Greenwood, HE, Barber, AR, Edwards, RS, Tyrrell, WE, George, ME, Dos Santos, SN, Baark, F, Tanc, M, Khalil, E, Falzone, A, Ward, NP, DeBlasi, JM, Torrente, L, Soni, PN, Pearce, DR, Firth, G, Smith, LM, Vilhelmsson Timmermand, O, Huebner, A, Swanton, C, Hynds, RE, DeNicola, GM & Witney, TH 2024, 'Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography', Nature Communications, vol. 15, no. 1, 10484. https://doi.org/10.1038/s41467-024-54852-4

TY - JOUR

T1 - Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography

AU - Greenwood, Hannah E

AU - Barber, Abigail R

AU - Edwards, Richard S

AU - Tyrrell, Will E

AU - George, Madeleine E

AU - Dos Santos, Sofia N

AU - Baark, Friedrich

AU - Tanc, Muhammet

AU - Khalil, Eman

AU - Falzone, Aimee

AU - Ward, Nathan P

AU - DeBlasi, Janine M

AU - Torrente, Laura

AU - Soni, Pritin N

AU - Pearce, David R

AU - Firth, George

AU - Smith, Lydia M

AU - Vilhelmsson Timmermand, Oskar

AU - Huebner, Ariana

AU - Swanton, Charles

AU - Hynds, Robert E

AU - DeNicola, Gina M

AU - Witney, Timothy H

PY - 2024/12/17

Y1 - 2024/12/17

N2 - 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.

AB - 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.

KW - Carcinoma, Non-Small-Cell Lung/diagnostic imaging

KW - Animals

KW - NF-E2-Related Factor 2/metabolism

KW - Humans

KW - Lung Neoplasms/diagnostic imaging

KW - Positron-Emission Tomography/methods

KW - Mice

KW - Cell Line, Tumor

KW - Female

KW - Kelch-Like ECH-Associated Protein 1/metabolism

KW - Fluorine Radioisotopes

KW - Radiopharmaceuticals

U2 - 10.1038/s41467-024-54852-4

DO - 10.1038/s41467-024-54852-4

M3 - Article

C2 - 39690148

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 10484

ER -