Differential ADAR1 Dependency in Breast Cancer Reveals Therapeutic Opportunities Through Regulation of MDM2 and Ferroptosis
Abstract
We aim to examine hypotheses that the ADAR1-MDM2 signaling axis could 1) mediate TNBC-associated ADAR1-dependency through ferroptotic cell-death; 2) induce MDM2-addiction and sensitize breast cancer cells to MDM2-inhibition therapy, depending on breast cancer subtypes. To maximize the potential clinical utility and translational impact, we will incorporate high-throughput drug screening to identify drug candidates, from FDA approved drug libraries, to provide proof-of-concept of ferroptosis-based therapeutic strategies against breast cancer. We hope to achieve both the short-term-goal of re-purposing existing drugs to demonstrate and amplify the clinical effect, and the long-term-goal of establishing a sustainable research program to highlight an innovative strategy against hard-to-treat breast cancers. In this second year, we have shown that ADAR1 protects TNBC from ferroptosis through regulating lipid remodeling and altering abundance of PUFA. We have discovered that ADAR1loss sensitizes TNBC to ferroptosis and MDM2 is a potential contributor to ADAR1-regulated ferroptosis sensitizing.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2023
- Accession Number
- AD1206962
Entities
People
- Jason D Weber
Organizations
- Washington University in St. Louis