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Nat Commun. 2019 Sep 13;10(1):4190. doi: 10.1038/s41467-019-12164-y.

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

Author information

1
Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
2
Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia.
3
Epigenetics and Development Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
4
Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
5
School of Life Sciences, Fudan University, Shanghai, China.
6
Department of Biochemistry and Molecular Biology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, 3052, Australia.
7
School of Life Sciences, Nanjing University, Nanjing, 210023, China.
8
Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
9
Department of Anatomical Pathology, St Vincent's Hospital, The University of Melbourne, Fitzroy, VIC, 3065, Australia.
10
Department of Surgery, St Vincent's Hospital, The University of Melbourne, Fitzroy, VIC, 3065, Australia.
11
School of Mathematics and Statistics, The University of Melbourne, Parkville, VIC, 3052, Australia.
12
Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. sutherland.k@wehi.edu.au.
13
Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia. sutherland.k@wehi.edu.au.

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 pathway, inhibition of which, using 6-AN, abrogated tumor growth. These studies highlight alternative therapeutic approaches to specifically target this unique subset of KRAS-mutant LUAD cancers.

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