Author of

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  MA24 - Genomic Evolution, KEAP 3 and More Non-Coding RNA (ID 928)

  • Event: WCLC 2018
  • Type: Mini Oral Abstract Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/26/2018, 10:30 - 12:00, Room 205 BD

  • 26185

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    MA24.09 - Synergy Between the KEAP1/NRF2 and PI3K Pathways Drives Non-Small Cell Lung Cancer with an Altered Metabolism (ID 13734)

    11:30 - 11:35  |  Author(s): Daniel H Gray
    • Abstract
    • Presentation
    • Slides

    Background
    

    The lung is a highly oxidative environment, tolerated through the engagement of tightly controlled stress response pathways. A critical stress response mediator is the transcription factor Nuclear Factor Erythroid-2-Related Factor 2 (NFE2L2/NRF2), which is negatively regulated by Kelch-like ECH-Associated Protein 1 (KEAP1). Alterations in the KEAP1/NRF2 pathway have been identified in 23% of lung adenocarcinomas, suggesting that deregulation of the pathway is a major driver in lung cancer.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    We generated a novel genetically engineered mouse model (GEMM) whereby Keap1 (Keap1^f/f) and Pten (Pten^f/f) were conditionally deleted in the lung, utilising intranasal inhalation of Adenovirus-Cre. The effects on lung pathology were investigated using histopathology, metabolomics and flow cytometry.

    4c3880bb027f159e801041b1021e88e8 Result
    

    We found that, while loss of Keap1 alone displayed no abnormalities in the lung, loss of Keap1 combined with loss of the tumour suppressor Pten, promoted malignant transformation. We further monitored tumour progression and immune infiltration in the lung, and metabolite profile changes in the serum of the Keap1^f/f/Pten^f/f mouse model. Notably, a tumour-specific metabolite signature was identified in the plasma of Keap1^f/f/Pten^f/f tumour-bearing mice, which indicated that tumourigenesis is associated with metabolic reprogramming. Furthermore, the immune milieu was dramatically changed by Keap1 and Pten deletion, and tumour regression was achieved utilising immune checkpoint inhibition.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Our study highlights the ability to exploit both metabolic and immune characteristics in the detection and treatment of lung adenocarcinomas harbouring KEAP1/NRF2 pathway alterations.

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