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Oxidative Stress, Metabolic Adaptation and Cancer Therapeutic Resistance


In normal cells, under homeostatic conditions, Nrf2 is kept off, as result of binding with its inhibitor Keap1. Constitutive activation of Nrf2 signaling in cancer cells upregulates the expression of cytoprotective antioxidant genes, drug detoxification enzymes and confers resistance against chemotherapy, radiation therapy, and promotes tumorigenicity.  Our initial report had shown that loss of function of KEAP1 due to mutations and LOH causes gain of Nrf2 function in non-small cell lung cancer. Following our initial report, we and others have shown that gain of Nrf2 function occurs in cancers such as prostate, skin, gall bladder, pancreas, ovary, esophagus, and breast cancer. Recently, oncogenic activating mutations in Nrf2 have been reported in various cancers including squamous carcinoma. Reduction of Nrf2 expression in cancer cells by RNAi induces generation of reactive oxygen species, suppresses tumor growth, and increases sensitivity to chemotherapeutic drug and ionizing radiation-induced cell death in preclinical cancer models. In patients with lung cancer, gain of Nrf2 function is associated with poor survival and resistance to platinum-based adjuvant chemotherapy. Collectively, these studies identified and validated Nrf2-KEAP1 axis as a novel therapeutic target in cancer. Several hit compounds have been identified as small molecule inhibitor of Nrf2 after screening ~400,000 compounds. Preclinical studies are in progress for developing the lead candidate prior to clinical trial. The laboratory is studying the interaction between Nrf2-keap1 signaling and well known oncogenes in various cancers using patient derived xenograft and GEM models.

Selected Publications