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

Author

Listed:
  • Hannah E. Greenwood

    (King’s College London, St Thomas’ Hospital)

  • Abigail R. Barber

    (King’s College London, St Thomas’ Hospital)

  • Richard S. Edwards

    (King’s College London, St Thomas’ Hospital)

  • Will E. Tyrrell

    (King’s College London, St Thomas’ Hospital)

  • Madeleine E. George

    (King’s College London, St Thomas’ Hospital)

  • Sofia N. Santos

    (King’s College London, St Thomas’ Hospital)

  • Friedrich Baark

    (King’s College London, St Thomas’ Hospital)

  • Muhammet Tanc

    (King’s College London, St Thomas’ Hospital)

  • Eman Khalil

    (King’s College London, St Thomas’ Hospital)

  • Aimee Falzone

    (H. Lee Moffitt Cancer Center)

  • Nathan P. Ward

    (H. Lee Moffitt Cancer Center)

  • Janine M. DeBlasi

    (H. Lee Moffitt Cancer Center)

  • Laura Torrente

    (H. Lee Moffitt Cancer Center)

  • Pritin N. Soni

    (H. Lee Moffitt Cancer Center)

  • David R. Pearce

    (UCL Cancer Institute, University College London
    The Francis Crick Institute)

  • George Firth

    (King’s College London, St Thomas’ Hospital)

  • Lydia M. Smith

    (King’s College London, St Thomas’ Hospital)

  • Oskar Vilhelmsson Timmermand

    (King’s College London, St Thomas’ Hospital)

  • Ariana Huebner

    (UCL Cancer Institute, University College London
    The Francis Crick Institute)

  • Charles Swanton

    (UCL Cancer Institute, University College London
    The Francis Crick Institute)

  • Robert E. Hynds

    (UCL Cancer Institute, University College London
    The Francis Crick Institute)

  • Gina M. DeNicola

    (H. Lee Moffitt Cancer Center)

  • Timothy H. Witney

    (King’s College London, St Thomas’ Hospital)

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.

Suggested Citation

  • Hannah E. Greenwood & Abigail R. Barber & Richard S. Edwards & Will E. Tyrrell & Madeleine E. George & Sofia N. Santos & Friedrich Baark & Muhammet Tanc & Eman Khalil & Aimee Falzone & Nathan P. Ward , 2024. "Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54852-4
    DOI: 10.1038/s41467-024-54852-4
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    References listed on IDEAS

    as
    1. Robert E. Hynds & Ariana Huebner & David R. Pearce & Mark S. Hill & Ayse U. Akarca & David A. Moore & Sophia Ward & Kate H. C. Gowers & Takahiro Karasaki & Maise Al Bakir & Gareth A. Wilson & Oriol Pi, 2024. "Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    2. Alexander M. Frankell & Michelle Dietzen & Maise Al Bakir & Emilia L. Lim & Takahiro Karasaki & Sophia Ward & Selvaraju Veeriah & Emma Colliver & Ariana Huebner & Abigail Bunkum & Mark S. Hill & Krist, 2023. "The evolution of lung cancer and impact of subclonal selection in TRACERx," Nature, Nature, vol. 616(7957), pages 525-533, April.
    3. Carlos Martínez-Ruiz & James R. M. Black & Clare Puttick & Mark S. Hill & Jonas Demeulemeester & Elizabeth Larose Cadieux & Kerstin Thol & Thomas P. Jones & Selvaraju Veeriah & Cristina Naceur-Lombard, 2023. "Genomic–transcriptomic evolution in lung cancer and metastasis," Nature, Nature, vol. 616(7957), pages 543-552, April.
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