Research Projects

Lung cancer is the leading cause of cancer-related deaths in India and worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. The transcription factor NRF2 transactivates its genes through antioxidant-responsive elements (AREs) and regulates oxidative stress in the human body. Mutations in the NFE2L2 gene (encoding the NRF2 protein) and its negative regulator gene KEAP1 occur in 20–30% of NSCLC. Deregulation of the NRF2 signaling pathway due to these mutations leads to cancer progression and resistance to chemo/radio/immuno-therapies. My previous work and others have shown that the hyperactivation of NRF2 pathway leads to poor prognosis in lung cancer. Thus, there is a need to search for downstream target genes and biomarkers of the NRF2 signaling pathway in NSCLC. Furthermore, the development of new or existing therapeutics to overcome treatment resistance in patients with KEAP1/NFE2L2 mutations is much needed. UDP-glucuronosyltransferases (UGTs) are the major enzymes responsible for the elimination of xenobiotics in our body, including chemotherapeutic agents. Dysregulation of UGTs expression and activity is associated with the chemoresistance of several cancers, and it is unclear how altered UGT activity affects tumor biology. Previous studies in rodent liver have shown that UGTs may be regulated by NRF2. However, functional studies on how NRF2 regulates UGTs, specifically in lung cancer have not been identified. Most importantly, my recent preliminary in silico and in vitro work shows that a group of UGTs are highly upregulated in NRF2-activated lung cancers. In this proposed project, I aim to investigate the potential involvement of NRF2 in induction of UGT genes in lung cancer and validate the UGTs as predictive biomarkers of the NRF2 signaling pathway. To examine the potential involvement of NRF2 in UGTs regulation, we will perform a series of in vitro experiments including ARE- luciferase reporter assay, and NRF2 siRNA/shRNA knockdown. Target genes and protein expressions will be evaluated in cell lines and patient biopsy samples. In addition, we will screen the patients for KEAP1/NFE2L2 mutations and correlate with UGTs expression and clinical outcomes. Finally, we will screen the FDA-approved drugs to inhibit NRF2 and its target UGTs. Our research will uncover the mechanism behind UGTs' NRF2-dependent expression and how it contributes to drug resistance and drug repurposing of FDA-approved drugs to inhibit the NRF2 pathway in lung cancer