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

Best, Ding, Kersbergen, Dong, Song, Xie, Reljic, Li, Vince, Rathi, Wright, Ritchie, Sutherland (2019) Distinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma Nat Commun (IF: 16.6) 10(1) 4190

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.

Links

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744438
http://www.ncbi.nlm.nih.gov/pubmed/31519898
http://dx.doi.org/10.1038/s41467-019-12164-y

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