NRF2-addicted Cancer: From Classical Experimental Animal Models toward Diagnosis and Treatment

Abstract

Cancer formation needs “optimum soil” in cellular microenvironment. ”Cell Competition” is an interesting mechanism in which mutated cells are eliminated by the surrounding normal cells. Professor Emanuel Farber and his colleagues at University of Toronto, Canada, demonstrated that carcinogens bind to genomic DNA, which then create specific DNA adducts to form tumors. This is the Resistant Hepatocyte rat model (also called as Solt-Farber model) established in 1970’s. This “Chemical Carcinogenesis” model is a combination of diethylnitrosamine (DEN), a tumor initiator, a proliferation inhibitor AAF and 70% partial hepatectomy that enhances proliferation, resulting in liver tumors. Preneoplastic lesions emerged in such a severe environment are consisted of hepatocytes positive to glutathione S-transferase P (GSTP). Professor Amedeo Columbano at University of Cagliari, Italy, who was a postdoctoral researcher in Farber’s laboratory reported in 2010’s that somatic mutations in NRF2 accumulated in the GSTP-positive lesions. The gain-of function mutations in NRF2 confer cells an ability to activate NRF2 constitutively. GSTP is a target gene of a transcription factor NRF2. On the other hand, somatic mutations in NRF2 and KEAP1 that regulates NRF2 activation have been reported in human cancer cells since 2006. As NRF2-addicted cancers occupy approximately 30% in certain types of cancers, such as in lung and esophagus, NRF2-targeting drugs would be critically important for the future therapies specific to the patients with NRF2-addicted cancers.