Alternative Polyadenylation as a Novel Mediator of Therapeutic Resistance in Lung Cancer
Abstract
This application addresses the FY20 LCRP Area of Emphasis to understand mechanisms of resistance to treatment (primary and secondary). Lung cancer is the leading cause of cancer-related death in the United States among both military Veterans and the general population. Over the past decade, significant improvements have been made in the treatment of advanced lung cancer. These improvements are mainly due to the development of targeted therapies, such as those directed against the Epidermal Growth Factor Receptor (EGFR). While most tumors initially respond to these new therapies, many soon develop resistance and recur, often increasing in aggressiveness. Due to the onset of drug resistance, the 5-year overall survival for patients with advanced disease remains low. Through an understanding of how tumors can develop resistance to therapies such as EGFR inhibitors, we hope to be able to effectively prevent or treat tumor recurrence and thereby extend patient life. Here we propose to identify a new mechanism of drug resistance called alternative polyadenylation. We discovered that genes regulating alternative polyadenylation are altered in drug-resistant lung cancer cells. We will study how the process of alternative polyadenylation promotes drug resistance and determine whether blocking alternative polyadenylation can render tumor cells more sensitive to treatment. This research is applicable to all patients with drug-resistant lung cancer in both the civilian and military populations. The current study is too basic for rapid clinical use, but may lead to eventual clinical trials combining EGFR inhibitors with inhibitors of alternative polyadenylation within 5 years. This study also represents a major advance in the field of drug resistance, with the possibility of translating the knowledge gained to other tumor types.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110646
Entities
People
- Pamela Hershberger
Organizations
- United States Army