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

ABSTRACT

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.

KEYWORDS:

• Keap1
• Nrf2
• lung
• adenocarcinoma
• targets

Article highlights

• Alterations in Nrf2 or Keap1 occurs in 18% (436 out of 2455 patients) of lung adenocarcinoma, and a ratio of 15% (379 out of 2455) mutations takes places in KEAP1.

• Aberrant methylation of KEAP1 contributed to drug/radiation resistance and tumor progression in lung adenocarcinoma. The suppression of KEAP1 methylation may sensitize other chemotherapy agents.

• In lung adenocarcinoma, miRNAs can bind and facilitate the degradation of KEAP1-NRF2 mRNA, most frequently via targeting the 3’ untranslated regions.

• Nrf2 can be negatively regulated by EZH2, which works as a downstream effector of KRAS signaling, indicating a feasible therapeutic strategy that combining PI3K targeted therapy with Nrf2 activation in lung adenocarcinoma with KRAS mutant.

• Energy homeostasis may crosstalk with Keap1-Nrf2 pathway, thus providing a rationale to design feasible combinatorial therapies.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial relationship or otherwise to disclose.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported by National Natural Science Foundation of China [81703629]; Science and Technology Project of Zhejiang Province [2012C23073]; Clinical Pharmacy of Zhejiang Medical Key Discipline [2018-2-3].