Journal article

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

Sarah A Best, David P De Souza, Ariena Kersbergen, Antonia N Policheni, Saravanan Dayalan, Dedreia Tull, Vivek Rathi, Daniel H Gray, Matthew E Ritchie, Malcolm J McConville, Kate D Sutherland

CELL METABOLISM | CELL PRESS | Published : 2018

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..

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Grants

Awarded by Worldwide Cancer Research Project grant


Awarded by Australian Health and Medical Research Council (NHMRC)


Awarded by Victorian Cancer Agency (VCA) Early Career Seed Grant


Funding Acknowledgements

We are grateful to C. Alvarado, L. Scott, K. Birchall, and L. Mackiewicz for animal husbandry; S. Monard for flow cytometry assistance; E. Tsui and C. Tsui in the WEHI Histology Facility for expert support; S. Carpineteri, C. Bowen (Shimadzu Australia), and V. Narayana (Metabolomics Australia) for technical assistance; and L. O'Rielly for CD8 antibody. We are thankful to A. Cox, J. Vissers (Peter MacCallum Cancer Centre), A. Berns, and P. Krimpenfort (Netherlands Cancer Institute) for critical reading of the manuscript and J. Visvader for useful discussions. This work was supported by a Worldwide Cancer Research Project grant (14-0433) and in part by an Australian Health and Medical Research Council (NHMRC) grant to K.D.S. and M.E.R. (1138275). S.A.B. is supported by a Victorian Cancer Agency (VCA) Early Career Seed Grant (ECSG16001); K.D.S. is supported by the Peter and Julie Alston Centenary Fellowship. M.J.M. is an NHMRC Principal Research Fellow. This work was made possible through Victorian Government Operational Infrastructure Support and the Australian government.