Targeting the cell signaling pathway Keap1-Nrf2 as a therapeutic strategy for adenocarcinomas of the lung

Introduction: Kelch-like ECH associated protein 1/Nuclear factor erythroid 2-like factor 2 (Keap1-Nrf2) signaling plays a pivotal role in response to oxidative stress in lung cancer. Mutations in KEAP1/NFE2L2 genes always cause persistent Nrf2 activation in lung cancer cells that confer therapeutic resistance and aggressive tumorigenic activity, dictating either poor prognosis or short duration of response to chemotherapy in clinical observations. Areas covered: We provide a review of the mechanisms underlying the regulation of Keap1-Nrf2 at different stages, including genetic mutations, epigenetic modifications, translational/post-translational alterations, and protein-protein interactions. Based on the current knowledge, we discuss the possibilities of intervening Keap1-Nrf2 in lung adenocarcinoma as a therapeutic target. Expert opinion: It is prevalently conceived that Keap1-Nrf2 signaling plays different roles at diverse stages of cancer. Although various Nrf2 or Keap1 inhibitors have been reported during the last decades, none of these inhibitors are currently under clinical studies or in clinical applications, suggesting that sole inhibition of Nrf2 might not be sufficient to suppress tumor growth. 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.