Overall, these findings elucidate the adaptive advantage provided by KEAP1/NRF2 pathway activation in KL tumors and support clinical testing of glutaminase inhibitor in subsets of KRAS-mutant lung adenocarcinoma.
On the basis of current studies, we suggest that the rational combination of Nrf2 suppression with chemical agents which cause enhanced oxidative imbalance or abnormal metabolism would be promising in the treatment of lung adenocarcinoma.
We also did a brief analysis of The Cancer Genome Atlas (TCGA) data of lung adenocarcinoma concerning the effects of radiation therapy and found that the therapy-induced Nrf2 activation is not universal.
Second, gene expression-based subtyping revealed three molecular subsets of KEAP1/NRF2-mutant lung adenocarcinomas and two molecular subsets of KEAP1/NRF2-mutant lung squamous cell carcinomas, each associated with distinguishing genetic, differentiation, immunological and clinicopathological properties.
Finally, we discovered the gene signature associated with <i>KEAP1</i> mutations, prognostic genes which were highly correlated with the upregulation of the NRF2 pathway in the KEAP1 mutated LUAD patients.
Here, the lung adenocarcinoma cell line A549 with constitutively expressed Nrf2 was found to be more tolerant to H<sub>2</sub>O<sub>2</sub> (0.1, 0.2, 0.5 and 1 mM) than normal lung cell line L132 or p53 null lung cancer cell line H1299.
Alterations in the KEAP1/NRF2 pathway have been identified in 23% of lung adenocarcinomas, suggesting that deregulation of the pathway is a major cancer driver.