Journal article

Distinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma

Sarah A Best, Sheryl Ding, Ariena Kersbergen, Xueyi Dong, Ji-Ying Song, Yi Xie, Boris Reljic, Kaiming Li, James E Vince, Vivek Rathi, Gavin M Wright, Matthew E Ritchie, Kate D Sutherland

NATURE COMMUNICATIONS | NATURE PUBLISHING GROUP | Published : 2019

Abstract

The KRAS oncoprotein, a critical driver in 33% of lung adenocarcinoma (LUAD), has remained an elusive clinical target due to its perceived undruggable nature. The identification of dependencies borne through common co-occurring mutations are sought to more effectively target KRAS-mutant lung cancer. Approximately 20% of KRAS-mutant LUAD carry loss-of-function mutations in KEAP1, a negative regulator of the antioxidant response transcription factor NFE2L2/NRF2. We demonstrate that Keap1-deficient KrasG12D lung tumors arise from a bronchiolar cell-of-origin, lacking pro-tumorigenic macrophages observed in tumors originating from alveolar cells. Keap1 loss activates the pentose phosphate pathwa..

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Grants

Awarded by Australian National Health and Medical Research Council (NHMRC)


Awarded by Victorian Cancer Agency Mid-Career Research Fellowship


Funding Acknowledgements

We are grateful to S. Oliver, C. Alvarado, L. Scott, S. O'Connor for animal husbandry, S. Monard in the WEHI Flow Cytometry Facility and E. Tsui in the WEHI Histology Facility for expert support. We acknowledge P. Maltezos in the WEHI Graphics Department for the design and preparation of figure illustrations. We thank R. K. Thomas (Department of Translational. Genomics, University of Cologne) for sequencing data for the Melbourne cohort of the CLCGP. We are thankful to A. Berns, A. Strasser and J. Vissers for critical reading of the manuscript and J. Visvader for useful discussions. This work was supported by an Australian National Health and Medical Research Council (NHMRC) Project Grant to K.D.S. and M.E.R. (1138275), S.A.B (1159002), and Career Development Fellowship to M.E.R. (1104924). K.D.S. is supported by a Victorian Cancer Agency Mid-Career Research Fellowship (18003) and the Peter and Julie Alston Centenary Fellowship; S. D. was supported by an Alan W. Harris Scholarship. This work was made possible through Victorian Government Operational Infrastructure Support and Australian Government.