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 first year, we have shown that ADAR1 protects TNBC from iron-dependent metabolic cell death. We have discovered that ADAR1 loss sensitizes TNBC to ferroptosis andMDM2 is a potential contributor to ADAR1-regulated ferroptosis sensitization.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2022
- Accession Number
- AD1191140
Entities
People
- Jason D Weber
Organizations
- Washington University in St. Louis