Distinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma
- Author(s)
- Best, SA; Ding, S; Kersbergen, A; Dong, X; Song, JY; Xie, Y; Reljic, B; Li, K; Vince, JE; Rathi, V; Wright, GM; Ritchie, ME; Sutherland, KD;
- 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
- Research Division(s)
- Cancer Biology And Stem Cells; Epigenetics And Development; Inflammation
- PubMed ID
- 31519898
- Publisher's Version
- https://doi.org/10.1038/s41467-019-12164-y
- Open Access at Publisher's Site
https://doi.org/10.1038/s41467-019-12164-y- NHMRC Grants
- NHMRC/1138275, NHMRC/1104924,
- Terms of Use/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