Distinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma
Details
Publication Year 2019-09-13, Volume 10, Issue #1, Page 4190
Journal Title
Nature Communications
Publication Type
Journal Article
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 Kras(G12D) 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.
Publisher
Springer Nature
WEHI Research Division(s)
Cancer Biology And Stem Cells; Epigenetics And Development; Inflammation
PubMed ID
31519898
Open Access at Publisher's Site
https://doi.org/10.1038/s41467-019-12164-y
NHMRC Grants
NHMRC/1138275 NHMRC/1104924
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2019-09-20 10:16:25
Last Modified: 2019-11-25 11:48:01
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