Global Downstream Pathway Analysis Reveals a Dependence of Oncogenic NF-E2-Related Factor 2 Mutation on the mTOR Growth Signaling Pathway

In multicellular organisms, adaptive responses to oxidative stress are regulated by NF-E2-related factor 2 (NRF2), a master transcription factor of antioxidant genes and phase II detoxifying enzymes. Aberrant activation of NRF2 by either loss-of-function mutations in the Keap1 gene or gain-of-function mutations in the Nrf2 gene occurs in a wide range of human cancers, but details of the biological consequences of NRF2 activation in the cancer cells remain unclear. Here, we report that mutant NRF2 induces epithelial cell proliferation, anchorage-independent growth, and tumorigenicity and metastasis in vivo. Genome-wide gene expression profiling revealed that mutant NRF2 affects diverse molecular pathways including the mammalian target of rapamycin (mTOR) pathway. Mutant NRF2 upregulates RagD, a small G-protein activator of the mTOR pathway, which was also overexpressed in primary lung cancer. Consistently, Nrf2-mutated lung cancer cells were sensitive to mTOR pathway inhibitors (rapamycin and NVP-BEZ235) in both in vitro and an in vivo xenograft model. The gene expression signature associated with mutant NRF2 was a marker of poor prognosis in patients with carcinoma of the head and neck region and lung. These results show that oncogenic Nrf2 mutation induces dependence on the mTOR pathway during carcinogenesis. Our findings offer a rationale to target NRF2 as an anticancer strategy, and they suggest NRF2 activation as a novel biomarker for personalized molecular therapies or prognostic assessment. Cancer Res; 70(22); 9095-105. (C) 2010 AACR.