Cell Metabolism
Volume 27, Issue 4, 3 April 2018, Pages 935-943.e4
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Short Article
Synergy between the KEAP1/NRF2 and PI3K Pathways Drives Non-Small-Cell Lung Cancer with an Altered Immune Microenvironment

https://doi.org/10.1016/j.cmet.2018.02.006Get rights and content
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Highlights

  • Combined loss of Keap1 and Pten promotes lung adenocarcinoma (ADC) formation

  • Altered metabolic activity is detectable in the plasma of tumor-bearing mice

  • PD-L1+ Keap1f/f/Ptenf/f tumors respond to anti-PD-1/anti-CTLA-4 treatment

  • Keap1f/f/Ptenf/f tumors mimic the metabolic and tumor infiltrating lymphocyte profile of NQO1high human ADC

Summary

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

non-small-cell lung cancer
Keap1
Pten
Nrf2
Taldo1
PD-L1

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