Mechanistic Understanding of m6A Signaling for the Treatment of TSC and LAM
Abstract
In tumors associated with TSC (tuberous sclerosis complex) and LAM (lymphangioleiomyomatosis), an enzyme called mTORC1 is highly activated. mTORC1 (mechanistic target of rapamycin complex 1) induces many cellular processes that promote tumor growth and proliferation. Thus, drugs that block mTORC1 (such as rapamycin) have been used to treat TSC and LAM tumors. However, long-term treatment causes serious side effects and drug resistance, highlighting an urgent need to identify better therapeutic options. Recent studies have shown that targeting a specific downstream process resulting from mTORC1, instead of mTORC1 itself, can be a more efficient and specific therapeutic strategy. Genes in the human genome must be first transcribed into RNA to generate proteins, which in turn promote cell metabolism and growth, and have a myriad of effects in the body. Thus, RNA is a key messenger delivering the genetic information from DNA to proteins. However, recent studies show that RNA is not just a messenger, but is dynamically regulated in cells by chemical modifications. These modifications change RNA stability, as well as efficiency in producing proteins and location in the cell. Recent technological inventions have enabled scientists to detect such chemical modifications on RNA that encode genes responsible for enhancing or suppressing tumors in several cancer types, including leukemia, brain, breast, and lung cancer. However, we still don’t understand how RNA chemical modification is altered in TSC and LAM. Also, it is still unclear whether mTORC1 regulates this process to promote tumor growth. During our longstanding effort to investigate cellular processes that depend on mTORC1 signaling, we have found that mTORC1 activates an enzyme complex required for the formation of the most abundant RNA chemical modification, m6A (N6-adenosine methylation). Based on this exciting finding, during this grant period we will demonstrate for the first time that overactivated mTORC1 signaling in TSC and LAM cells chemically modifies RNA and thereby exacerbates tumor progression. We will primarily focus on kidney tumors in this project, but our findings have a potential to be applied to TSC tumors in other vital organs including brain, skin, eyes, and lungs. Our study’s success will open a new therapeutic possibility: targeting RNA modification enzymes as drug targets that are likely to be more selective than rapamycin. Also, it will determine the potential of using RNA modifications as biomarkers for overactive mTORC1 activity to diagnose tissue lesions that may develop into TSC and LAM tumors. We believe that our innovative basic research will help us make broad strides to better therapeutics for mTORC1-driven cancers including TSC and LAM.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110254
Entities
People
- Gina Lee
Organizations
- United States Army
- University of California, Irvine