Understanding and Blocking NRF2 Oncoprotein in Lung Cancer
Abstract
Background and Rationale: The ultimate goal of this project is to improve quality of life and implement new treatment options for lung cancer, which is one of the most lethal cancers with >150,000 deaths accounting for ~25% of cancer-associated deaths in the U.S. alone last year. Mutations in the NRF2 gene are found in ~30% of lung cancer patients, and these patients in particular carry very poor prognosis and are refractory to current treatment options. Notably, lung cancer patients carrying mutation in the NRF2 gene have substantially lower disease-free and overall survival. NRF2 protein helps cancer cells multiply by increasing their energy production, eliminating toxic byproducts, and escaping conventional anti-cancer therapies. Specifically, cells with NRF2 activation are more efficient at absorbing glucose from their environment, which help cancer cells grow by efficiently diverting glucose to different cellular metabolic and energy-producing pathways. However, glucose can attach itself on certain proteins and form a dysfunctional protein-glucose adduct through a process called glycation. Our cells contain an enzyme called fructosamine-3-kinase (FN3K) that removes glucose from glucoseprotein adducts to repair and restore protein function. NRF2 is a major protein that forms such glucose adducts (NRF2-glucose adducts) through glycation and can only be repaired by FN3K. In the absence of FN3K, most of the NRF2 protein remains fused to glucose, and this is deleterious to its cancer-promoting functions. Therefore, in principle strategies that inhibit FN3K will block NRF2 by preventing the removal of attached glucose and can be viable therapeutic options for lung cancers with NRF2 mutations. I propose to test this hypothesis using mouse models and human cell lines of lung cancer that have an NRF2 mutation. NRF2 is considered an undruggable protein; however, FN3K is highly amenable to chemical inhibitors, and this project is a first step in identifying new strategies of combating untreatable and aggressive NRF2-mutant lung cancers. This proposal addresses two emphasis areas of LCRP: (1) understanding the molecular mechanisms of initiation and progression of clinically significant lung cancer and (2) identify innovative strategies of treatment of lung cancer. Military Relevance: Lung cancer is a significant clinical problem amongst active military personnel and veterans because of higher overall incidence and lower survival compared to civilians. Two main reasons behind these alarming statistics are (1) the high propensity of developing a smoking habit compared to the general population and (2) constant exposure to harmful chemical warfare agents and carcinogenic particulate matters. In fact, lung cancer is the most common malignancy and a leading cause of cancer-associated deaths among current and retired military personnel, e.g., Vietnam and Gulf War Veterans have significantly higher rate of lung cancer incidence and deaths. Moreover, NRF2 protects cancer cells from harmful effects of repeated exposure to toxins and thereby promotes cancer survival and progression. Therefore, any strategy aimed at targeting NRF2 will hugely benefit active and retired military officers. While I do not expect to use any military resources the findings are far more applicable to military population give the higher incidence of them developing lung cancer. Clinical Application and Impact: This project is a first step to developing new and improved strategies, such as FN3K inhibition, to treat highly aggressive and therapeutically cold lung cancers. FN3K is highly amenable to synthetic drugs, and this project will lay a strong foundation towards their development. Beyond the clinical application, this research will also uncover new biology on the role of NRF2 in cancer and move the field forward. In summary, I propose a very novel project with immense therapeutic potential that will substantially improve patient care i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010549
Entities
People
- Viraj Sanghvi
Organizations
- Leonard M. Miller School of Medicine
- United States Army