Oxidative stress, metabolic adaptation and therapeutic resistance of cancer:
We discovered that non small cell lung cancer frequently develop gain of function in Nrf2 due to KEAP1 mutations, which increases antioxidants and alters metabolism to drive tumor growth and cause therapeutic resistance. This has changed the paradigm in cancer biology and develop our understanding of dark side of antioxidants in cancer cells. Our current effort will help unravel mechanisms of oncogenic cooperation and metabolic adaptation using patient-derived xenografts in humanized immunocompetent mice and GEM models.
Singh A, Venkannagari S, Oh KH, Zhang YQ, Rohde JM, Liu L, Nimmagadda S, Sudini K, Brimacombe KR, Gajghate S, Ma J, Wang A, Xu X, Shahane SA, Xia M, Woo J, Mensah GA, Wang Z, Ferrer M, Gabrielson E, Li Z, Rastinejad F, Shen M, Boxer MB, Biswal S. Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in KEAP1-Deficient NSCLC Tumors. ACS Chem Biol. 2016 PMID: 27552339.
Singh A, Happel C, Manna SK, Acquaah-Mensah G, Carrerero J, Kumar S, Nasipuri P, Krausz KW, Wakabayashi N, Dewi R, Boros LG, Gonzalez FJ, Gabrielson E, Wong KK, Girnun G, Biswal S. Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis. J Clin Invest. 2013 PMID: 23921124.
Singh A, Boldin-Adamsky S, Thimmulappa RK, Rath SK, Ashush H, Coulter J, Blackford A, Goodman SN, Bunz F, Watson WH, Gabrielson E, Feinstein E, Biswal S. RNAi-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy. Cancer Res. 2008 PMID: 18829555.
Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, Hoque MO, Herman JG, Baylin SB, Sidransky D, Gabrielson E, Brock MV, Biswal S. Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med. 2006 PMID: 17020408.