A Small Molecule That Targets the KEAP1/NRF2 Signaling Pathway in Lung Cancer
Abstract
Lung cancer is the leading cause of cancer-related mortality in the United States, causing approximately 150,000 deaths in the United States each year. Each lung cancer has specific genetic changes that drive its growth and spread. A great deal of attention is focused on designing drugs that target these mutated genes and have limited effects on the rest of the cells in the body. One example of the success of this strategy has been the development of erlotinib (Tarceva) for patients whose tumor have genetic changes in the epidermal growth factor receptor (EGFR) gene. In these patients, erlotinib induces dramatic responses with relatively minor side effects. Unfortunately, many patients develop resistance to this therapy when their tumor acquires mutations in other genes. In this proposal, we seek to target lung cancers that have mutations in a gene called KEAP1. This gene mutation is the third most commonly mutated gene in lung cancer, leading to resistance to chemotherapy, radiation therapy, and drugs like erlotinib. At this time, there are no drugs that target lung cancers that have KEAP1 mutations. Our laboratory has identified a compound that selectively kills cancer cells that have mutations in KEAP1, but spares healthy cells (which do not have these mutations). This proposal seeks to establish whether this drug can specifically decrease the growth of lung cancer cells with KEAP1 mutations. We will evaluate whether this drug, as well as several new derivatives of this drug, can suppress the growth of lung cancers in mice. Finally, we will determine whether this drug can overcome the resistance of tumors that no longer respond to drugs like erlotinib. Our studies could establish the basis for the development of a new therapy that inhibits the growth of nearly one-third of lung cancers. Such a treatment could be useful to improve the survival of a large population of civilians and military Service members with lung cancer, who have otherwise limited options for therapy. We anticipate that our studies, if successful, could catalyze the clinically meaningful pharmaceutical development of drug candidates within 5 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010381
Entities
People
- Rizwan Haq
Organizations
- Dana–Farber Cancer Institute
- United States Army