Differential ADAR1 Dependency in Breast Cancer Reveals Therapeutic Opportunities Through Regulation of MDM2 and Ferroptosis
Abstract
Rationale: Receiving a cancer diagnosis is one of the most difficult moments one could experience. For a breast cancer patient, 1 in nearly 300,000 per year in the U.S., what the following biopsy reveals has a huge impact on the prognosis. For 80% of breast cancer patients, whose cancer biopsies have strong expression of either ER or HER2, a clear course of action becomes available thanks to proven targeted therapies. ER modulators (e.g., Tamoxifen and Fulvestrant) and HER2-targeting antibodies (e.g., Herceptin) provide significant survival benefit to render these cases manageable chronic diseases. However, about 30% of these patients eventually experience disease recurrence, often due to development of drug resistance (endocrine resistance) and metastasis. These options are not even afforded to the remaining patients with triple-negative breast cancer (TNBC, with absence of ER, HER2, and PR). Without targeted therapies, chemotherapy with a confusing variety of drug combinations is the standard of care for TNBC upon diagnosis. For patients with TNBC and endocrine-resistant breast cancer, physicians often have to make “educated guesses” when forced to replace ineffective treatment upon disease progression. Severe side effects, combined with the unpredictability of outcomes, place huge physical, mental, and financial burdens on cancer patients and their caregivers. Novel therapies that are tailorable based on subtypes to overcome drug resistance for these patients will be a huge relief. Objective: We recently discovered a novel pathway that is regulated differently between TNBC and non-TNBC. By removing one gene, ADAR1, TNBC cells stop growing, while non-TNBC cells show no difference. Interestingly, by looking at genes changed in the absence of ADAR1, we found that one gene, MDM2, is consistently expressed at a higher level in all cell lines, regardless of subtypes. MDM2 is known to have both cancer-promoting and cancer-stopping activities, and we hypothesize that higher expression of MDM2, while helping to kill TNBC in the absence of ADAR1, provides a new bullseye target for cancer therapy in non-TNBC, since multiple MDM2 inhibitors, after years of development, are already in clinical trials for cancer treatment. Specific Aims: 1. To investigate if ADAR1 loss sensitizes TNBC cells to MDM2-mediated ferroptosis. 2. To investigate if ADAR1 loss sensitizes non-TNBC cells to MDM2 inhibition. Applicability: In the first aim, we will determine if TNBC can’t survive the loss of ADAR1 because of the increased expression of MDM2. We will investigate one specific pathway, ferroptosis, that is a new mechanism to trigger cell destruction. More importantly, we will conduct the first known drug screen to identify a ferroptosis-inducer in TNBC, by using a collection of FDA-approved drugs. It means that a positive identification will lead to a quick transition into clinical studies to repurpose an existing drug to treatment TNBC patients through a novel, and potentially more effective strategy. In the second aim, we will unveil a genetic weak spot exposed by the removal of ADAR1. The concept of synthetic lethality, meaning combining multiple drugs to kill cancer cells, is a promising strategy to develop cancer. Removal of ADAR1, although it does not kill non-TNBC cells, results in high MDM2 expression. We will test the possibility of treating these cells with MDM2 inhibitors after removal of ADAR1. If successful, we will discover an intriguing synthetic lethality treatment opportunity. MDM2 inhibitors have been tried to treat breast cancers with poor efficacy. Researchers have suggested that it is due to the lack of MDM2 expression in breast cancer. Our finding could complete one-half of the puzzle. With several MDM2 inhibitors already in clinical trials and proven safe, as well as much effort currently ongoing to develop ADAR1 inhibitors, the ADAR1/MDM2 combination therapy could become an effective options for breast cancer pa
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110476
Entities
People
- Jason D Weber
Organizations
- United States Army
- Washington University in St. Louis