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

Best, SA; De Souza, DP; Kersbergen, A; Policheni, AN; Dayalan, S; Tull, D; Rathi, V; Gray, DH; Ritchie, ME; McConville, MJ; Sutherland, KD

Author(s): Best, SA; De Souza, DP; Kersbergen, A; Policheni, AN; Dayalan, S; Tull, D; Rathi, V; Gray, DH; Ritchie, ME; McConville, MJ; Sutherland, KD;
Details: Publication Year 2018,Volume 27,Issue #4,Page 935-943.e934
Journal Title: Cell Metabolism
Publication Type: Journal Article
Abstract: 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. Best et al. identify the tumorigenic potential of Nrf2 pathway activation in lung epithelium in the context of PI3K pathway alterations. Plasma metabolite profiling suggests that tumorigenesis is associated with reprogramming of the pentose phosphate pathway. Tumor-bearing lungs exhibit an altered immune milieu and are amenable to checkpoint inhibitor therapy. © 2018 Elsevier Inc.
Publisher: Cell Press
Research Division(s): Stem Cells And Cancer; Molecular Genetics Of Cancer; Molecular Medicine
PubMed ID: 29526543
Publisher's Version: https://doi.org/10.1016/j.cmet.2018.02.006
NHMRC Grants: NHMRC/1138275,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2018-03-19 10:02:29

Last Modified: 2018-06-05 01:37:47