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

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-li...

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Published in:	Cell metabolism Vol. 27; no. 4; p. 935
Main Authors:	Best, Sarah A, De Souza, David P, Kersbergen, Ariena, Policheni, Antonia N, Dayalan, Saravanan, Tull, Dedreia, Rathi, Vivek, Gray, Daniel H, Ritchie, Matthew E, McConville, Malcolm J, Sutherland, Kate D
Format:	Journal Article
Language:	English
Published:	United States 03.04.2018
Subjects:	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 Pentose Phosphate Pathway Phosphatidylinositol 3-Kinases - metabolism PTEN Phosphohydrolase - genetics PTEN Phosphohydrolase - metabolism PTEN Phosphohydrolase - physiology Keap1 PD-L1 Pten Nrf2 Taldo1 non-small-cell lung cancer
ISSN:	1932-7420, 1932-7420
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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 Keap1 /Pten 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1932-7420 1932-7420
DOI:	10.1016/j.cmet.2018.02.006