Signaling Mechanisms Mediating Targeted Therapy-Induced CXCL10 and MHC Class I Expression in Lung Adenocarcinoma
Abstract
The proposal addresses the Lung Cancer Research Program 2018 Areas of Interest, “Identifying innovative strategies for prevention and treatment of lung cancer,” and “Understanding predictive markers to identify responders and non-responders.” This project is relevant to military Service members, Veterans, and their families because lung cancer is the leading cause of cancer death in men and women. Service members and Veterans exhibit a higher rate of tobacco use relative to civilian populations, where tobacco smoking is the major cause of lung cancer incidence. This proposal focuses on lung cancers driven by oncogenic forms of epidermal growth factor receptor (EGFR) and KRAS. While EGFR-driven lung cancer is more frequent in non-smokers, it still occurs in smokers. By contrast, KRAS mutant lung cancer is more frequent in former and active tobacco smokers. Importantly, non-smoking related lung cancers still rank within the top 10 based on the number of cancer deaths; thus, the project is relevant to military Service members and Veterans, regardless of tobacco exposure. If successful, the project is predicted to exert a significant impact on the health and well-being of Service members, Veterans, and their families. The overall objective of this project is to explore and understand the responses of lung cancer cells to drugs that inhibit their driving oncogenes, in this case EGFR and KRAS. Our preliminary studies indicate that oncogene inhibitors stimulate the expression of proteins that are predicted to facilitate the participation of specific immune cells in the therapeutic response to the drugs. This response is also quite variable across different lung cancer cell lines and may account for why some lung cancer patients respond more strongly or weakly to therapies. A deeper understanding of this response may lead to rational strategies to enhance the anti-tumor effects of targeted drugs. We anticipate that positive findings will lead to novel and evidence-based strategies for improving the therapeutic outcome for patients bearing EGFR- and KRAS-driven lung cancers through combination with existing and emerging agents that enhance engagement of the patient’s immune system in the attack on their lung cancer. The most effective precision medicines for treatment of lung cancers driven by oncogenic forms of EGFR induce pronounced tumor shrinkage and increased patient survival, but some cancer cells invariably remain. This is important because these remaining tumor cells serve as a source for the outgrowth of lethal, drug-resistant cancers. By contrast, no targeted drugs are yet available for directly inhibiting mutant KRAS, although downstream signaling through specific pathways can be inhibited. The clinical applicability of the project may emerge upon a deeper understanding of how oncogene- and pathway-targeted drugs that disrupt tumorigenic signaling of EGFR and KRAS result in increased secretion of factors that actively recruit specific immune cells into the tumor, a potential therapeutic vulnerability. Ultimately, the results may lead to testing of combinations of existing and still emerging immune-based therapies and oncogene-targeted drugs to enhance anti-tumor responses in patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910635
Entities
People
- Lynn E Heasley
Organizations
- United States Army
- University of Colorado Denver