Authors: 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, Kate D. Sutherland
Summary: 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.
Source: Nature Communications, 2019; 10 (1)