The Therapeutic Role of lncRNA-Mediated DNA Repair in Lung Cancer
Abstract
Lung cancer causes over 150,000 American deaths each year, and almost 20% of Veterans will ultimately be diagnosed with lung cancer. The incidence of lung cancer is higher among Veterans than the non-Veteran population due to military exposures related to their military Service such as Agent Orange, radon, asbestos, beryllium, pesticides, burn pits, oil fires, and the destruction of chemical weapons. Sadly, Veterans have overall poorer outcomes than the non-Veteran population. Personalized medicine based on the etiology of the tumor brings exciting promise to move the needle and dramatically improve Veteran patient survival. Therefore, understanding the molecular underpinnings of which Veterans will benefit from a given treatment would represent a major breakthrough. Long non-coding RNAs are an emergent class of cellular regulators that have recently been ascribed many roles in cancer development. My laboratory has chosen to study lung adenocarcinoma, which is the most common type of lung cancer and, despite recent advances in treatment, still has an ~85% mortality rate. Previous work in my laboratory has uncovered the long non-coding RNA LINC00261 as a major influencer of lung adenocarcinoma development. LINC00261 acts as a tumor suppressor and affects DNA repair signaling; however, we do not fundamentally understand how this lncRNA interacts with and alters DNA damage repair. Errors in DNA repair lead to the accumulation of mutations. The cell is trained to recognize damaged DNA and stop cell replication to allow for DNA repair; however, cancer evades this process. As a secondary defense mechanism, the immune system can recognize when tumors accumulate mutations because cells are constantly presenting proteins to their surfaces in case they have viral or bacterial infections. Tumors evade this secondary mechanism by blocking the ability of immune cells to surveil the tumor. Immunotherapies are based on re-sensitizing the immune system to the tumors, but can fail if no mutated proteins are being presented at their surfaces. This proposal aims to answer fundamental questions about how this lncRNA regulates DNA damage pathway activation and what consequences of that activity are on tumor mutational burden and subsequent patient response to chemotherapeutics. In doing so, this project will address two areas of emphasis for the Department of Defense Lung Cancer Research Program (LCRP). First, studying how LINC00261 interacts with DNA repair machinery in lung adenocarcinoma will expand our knowledge in “understanding the mechanisms of initiation and progression to lung cancer.” Secondly, by understanding how LINC00261 affects resistance to platinum-based chemotherapies, we can predict which patients will respond to therapy, sparing those with chemo-resistant tumors unnecessary morbidities associated with off-target effects. Because we also observe a connection between LINC00261 and the ability of tumors to present proteins on their surface for immune surveillance, we will also be able to determine whether LINC00261 can be utilized as a biomarker for a tumor’s ability to be recognized by the immune system once treated with immunotherapy. These undertakings to understand LINC00261’s relationship to chemo- and immuno-therapeutic response address the “develop or optimize predictive biomarkers of therapeutic response” LCRP priority area. The ultimate applicability of this research will be to both obtain a deeper mechanistic understanding of how LINC00261 associates with DNA damage repair regulators and how this translates to the rate of DNA mutation and mutated protein presentation on the surface of tumor cells that can be used to develop enhanced clinical guidelines for Veterans independent of common driver mutations that are not present in all Veterans’ tumors. The accumulation of errors in DNA is the fundamental underlying phenomenon in the genesis of cancer; therefore, understanding how a cell prevents
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110231
Entities
People
- Crystal N Marconett
Organizations
- United States Army
- University of Southern California