Keap1–Nrf2 pathway: A promising target towards lung cancer prevention and therapeutics

Abstract

Objectives: Drugs for targeted therapy have become a new strategy of adjuvant therapy for treatment of lung cancer. The Keap1 (kelch-like ECH-associated protein 1)–Nrf2 (nuclear factor erythroid 2-related factor 2) pathway is recognized to be critical in regulating genes related to the cellular protective response and protecting cells from oxidative damages and toxic insult. Methods: Pubmed, Embase, OVID, and the Cochrane Library databases were searched from the beginning of each database without any limitations to the date of publication. Search terms were “Nrf2” or “Keap1” and “Lung cancer”. Results: The upregulation of Nrf2 had been closely related to tumor protection and drug resistance. The aberrant state of Keap1 or Nrf2 that were frequently found in lung cancer conferred a poor prognosis. Nrf2 could prevent cells from undergoing oncogenesis as a tumor suppressor, while it could also promote cancer progression and resistance to chemotherapeutic drugs as an oncogene, depending on the different stages of tumor progression. Target Nrf2 signaling by specific chemicals showed it could prevent tumor growth or combat chemoresistance. Conclusions: Increasing evidence has demonstrated the dual roles of the Keap1–Nrf2 pathway in tumor initiation and progression. In this paper, we provide a comprehensive overview of the potency of the Keap1–Nrf2 pathway as an antitumor target, and the current status of Nrf2 activators or inhibitors for therapeutic approaches. Further studies are required to clarify the role of Nrf2 in lung cancer at different tumor stages, in order to maximize the efficacy of Keap1–Nrf2 targeting agents. Keywords: Cancer prevention, Keap1, Lung cancer, Nrf2