Synergy between the KEAP1/NRF2 and PI3K Pathways Drives Non-Small-Cell Lung Cancer with an Altered Immune Microenvironment

Cell Metab. 2018 Apr 3;27(4):935-943.e4. doi: 10.1016/j.cmet.2018.02.006. Epub 2018 Mar 8.


The lung presents a highly oxidative environment, which is tolerated through 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 cancer driver. We demonstrate that inactivation of Keap1 and Pten in the mouse lung promotes adenocarcinoma formation. Notably, metabolites identified in the plasma of Keap1f/f/Ptenf/f tumor-bearing mice indicate that tumorigenesis is associated with reprogramming of the pentose phosphate pathway. Furthermore, the immune milieu was dramatically changed by Keap1 and Pten deletion, and tumor regression was achieved utilizing immune checkpoint inhibition. Thus, our study highlights the ability to exploit both metabolic and immune characteristics in the detection and treatment of lung tumors harboring KEAP1/NRF2 pathway alterations.

Keywords: Keap1; Nrf2; PD-L1; Pten; Taldo1; non-small-cell lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung / immunology
  • Adenocarcinoma of Lung / metabolism
  • Animals
  • Carcinogenesis
  • Carcinoma, Non-Small-Cell Lung* / immunology
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / genetics
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Kelch-Like ECH-Associated Protein 1 / physiology*
  • Loss of Function Mutation
  • Lung Neoplasms* / immunology
  • Lung Neoplasms* / metabolism
  • Mice, Mutant Strains
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • NF-E2-Related Factor 2 / physiology*
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • PTEN Phosphohydrolase / physiology*
  • Pentose Phosphate Pathway
  • Phosphatidylinositol 3-Kinases / metabolism*


  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Phosphatidylinositol 3-Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Pten protein, mouse