Flash Talk & Poster Presentation 30th Lorne Cancer Conference 2018

Synergy between the KEAP1/NRF2 and PI3K pathways drives non-small cell lung cancer with an altered metabolism (#202)

Sarah A Best 1 2 3 , David P DeSouza 4 , Ariena Kersbergen 3 , Vivek Rathi 5 , Saravanan Dayalan 4 , Dedreia Tull 4 , Antonia Policheni 2 6 , Daniel Gray 2 6 , Matthew E Ritchie 2 7 , Malcolm McConville 4 , Kate D Sutherland 1 2 3
  1. Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Medical Biology, Melbourne University, Melbourne, Victoria, Australia
  3. ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  4. Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, Melbourne, Victoria, Australia
  5. Anatomical Pathology, St Vincent's Hospital, Melbourne, Victoria, Australia
  6. Molecular Genetics of Cancer, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  7. Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia

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. Using genetically engineered mouse models (GEMMs), we conditionally deleted Keap1 (Keap1f/f) in the lung, utilising inhalation of Adenovirus-driven Cre, and investigated the effects on lung cancer development. 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 Keap1f/f/Ptenf/f GEMM. Notably, a tumour-specific metabolite signature was identified in the plasma of Keap1f/f/Ptenf/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. Thus, 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.