Lung cancer is the most common cause of cancer-related death worldwide and intrinsic therapeutic resistance of non small cell lung cancer (NSCLC) cells remains a major challenge in improving the effectiveness of cancer therapy. Nuclear factor erythroid-2 related factor-2 (Nrf2) is a redox-sensitive transcription factor that regulates the expression of electrophile/ xenobiotic detoxification enzymes and drug efflux proteins and confers cytoprotection against oxidative stress and apoptosis in normal cells. Kelch-like ECH-associated protein (Keap1) negatively regulates Nrf2 activity by targeting it for proteasomal degradation. We recently reported that biallelic inactivation of Keap1 results in constitutive activation of Nrf2 function in NSCLC. Preliminary studies indicate that constitutive activation of Nrf2 in lung cancer cells increases activity of central metabolic pathways, promotes in vivo tumor growth and contributes to chemoresistance. Thus, we hypothesize that the gain of Nrf2 function resulting from the loss of Keap1 activity promotes tumorigenesis and confers therapeutic resistance and wild type Keap1 functions as a tumor suppressor by inhibiting the activity of Nrf2.
Specific Aim 1 : To test the hypothesis that the gain of Nrf2 function promotes lung tumorigenesis (in the presence of an oncogenic signal).
Specific Aim 2 : To test the hypothesis that restoring wild type Keap1 function in NSCLC cells with high Nrf2 levels attenuates Nrf2 activity and suppresses tumor growth.
Specific Aim 3 : To test the hypothesis that the gain of Nrf2 function in lung cancer cells increases glucose flux through pentose phosphate pathway and Tricarboxylic acid cycle essential for promoting tumor growth.
Specific Aim : To test the hypothesis that blocking the activity of Nrf2-dependent phosphate pathway enzymes (Glucose-6 phosphate dehydrogenase and Transketolase) in NSCLC cells with gain of Nrf2 function inhibits tumor growth and attenuates chemoresistance.
These aims will help in understanding the regulation of lung tumorigenesis by a novel pathway and develop a strategy for targeting this pathway to circumvent therapeutic resistance.

Public Health Relevance

The studies proposed in this project have potential for developing new means to inhibit tumor progression and chemoresistance. Successful completion of this project will develop a new therapeutic strategy for lung cancer treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Forry, Suzanne L
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Johns Hopkins University
Public Health & Prev Medicine
Schools of Public Health
United States
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Singh, Anju; Venkannagari, Sreedhar; Oh, Kyu H et al. (2016) Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in KEAP1-Deficient NSCLC Tumors. ACS Chem Biol 11:3214-3225
Sussan, Thomas E; Gajghate, Sachin; Thimmulappa, Rajesh K et al. (2015) Exposure to electronic cigarettes impairs pulmonary anti-bacterial and anti-viral defenses in a mouse model. PLoS One 10:e0116861
Kim, Jung-Hyun; Thimmulappa, Rajesh K; Kumar, Vineet et al. (2014) NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation. J Clin Invest 124:730-41
Kombairaju, Ponvijay; Kerr, Jaclyn P; Roche, Joseph A et al. (2014) Genetic silencing of Nrf2 enhances X-ROS in dysferlin-deficient muscle. Front Physiol 5:57
Wang, Lei; Kondo, Naoshi; Cano, Marisol et al. (2014) Nrf2 signaling modulates cigarette smoke-induced complement activation in retinal pigmented epithelial cells. Free Radic Biol Med 70:155-66
Singh, Anju; Happel, Christine; Manna, Soumen K et al. (2013) Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis. J Clin Invest 123:2921-34
Kombairaju, Ponvijay; Ma, Jinfang; Thimmulappa, Rajesh K et al. (2012) Prolonged sulforaphane treatment does not enhance tumorigenesis in oncogenic K-ras and xenograft mouse models of lung cancer. J Carcinog 11:8
Kumar, Vineet; Kumar, Sarvesh; Hassan, Mohammad et al. (2011) Novel chalcone derivatives as potent Nrf2 activators in mice and human lung epithelial cells. J Med Chem 54:4147-59
Li, Qing Kay; Singh, Anju; Biswal, Shyam et al. (2011) KEAP1 gene mutations and NRF2 activation are common in pulmonary papillary adenocarcinoma. J Hum Genet 56:230-4
Merchant, Akil A; Singh, Anju; Matsui, William et al. (2011) The redox-sensitive transcription factor Nrf2 regulates murine hematopoietic stem cell survival independently of ROS levels. Blood 118:6572-9

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