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 and Kate D. Sutherland ()
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Sarah A. Best: The Walter and Eliza Hall Institute of Medical Research
Sheryl Ding: The Walter and Eliza Hall Institute of Medical Research
Ariena Kersbergen: The Walter and Eliza Hall Institute of Medical Research
Xueyi Dong: The University of Melbourne
Ji-Ying Song: The Netherlands Cancer Institute
Yi Xie: The Walter and Eliza Hall Institute of Medical Research
Boris Reljic: The University of Melbourne
Kaiming Li: The Walter and Eliza Hall Institute of Medical Research
James E. Vince: The University of Melbourne
Vivek Rathi: The University of Melbourne
Gavin M. Wright: The University of Melbourne
Matthew E. Ritchie: The Walter and Eliza Hall Institute of Medical Research
Kate D. Sutherland: The Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12164-y

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