Research Publications


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

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
Nature Communications
Journal Article
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.
Springer Nature
Cancer Biology and Stem Cells; Epigenetics and Development; Inflammation
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Creation Date 2019-09-20 10:16:25 Last Modified 2019-11-25 11:48:01