Aggressive Breast Cancer Has a New Weakness, Study Finds

Researchers at MUSC Hollings Cancer Center have identified a potential new strategy to combat one of the most aggressive forms of breast cancer, triple-negative breast cancer (TNBC). Their findings suggest that targeting two specific proteins within cancer cells could render them vulnerable to a process called ferroptosis, effectively triggering cell death through toxic damage. This discovery, published in Cell Reports Medicine, offers hope for more effective treatments for a disease that is notoriously difficult to manage. The research team, led by Ozgur Sahin, focused on how TNBC cells develop resistance to conventional therapies. Unlike other types of breast cancer, TNBC lacks estrogen and progesterone receptors and overexpresses HER2 protein, making it less responsive to targeted hormonal or antibody-based treatments. As a result, chemotherapy is frequently used post-surgery to prevent recurrence, though it carries risks of incomplete eradication and subsequent resistance. In many cases, even after successful initial treatment, cancer can return and become harder to treat. To address this challenge, the scientists explored ways to weaken TNBC’s ability to resist treatment. They tested an experimental LOX inhibitor, which blocks the activity of lysyl oxidase, a protein critical for maintaining structural integrity in cancer cells. By disrupting LOX, the researchers observed that TNBC cells lost some of their protective mechanisms, making them more susceptible to internal damage. To further weaken the cancer’s defenses, they combined the LOX inhibitor with leflunomide, an FDA-approved medication typically used to treat rheumatoid arthritis. Leflunomide inhibits the DHODH enzyme, which plays a role in cellular metabolism and immune response. Together, these interventions created conditions favorable for ferroptosis, a form of programmed cell death driven by oxidative stress and lipid peroxidation. The study demonstrated that blocking both LOX and DHODH significantly reduced tumor growth in preclinical models of TNBC. Notably, the treatment did not cause severe side effects such as weight loss or organ toxicity, unlike traditional chemotherapies. Additionally, the combination proved more effective than pairing the LOX inhibitor with a standard chemotherapy drug. The researchers also analyzed tumor samples from patients whose cancers had become resistant to chemotherapy. They found that tumors expressing high levels of both LOX and DHODH correlated with worse survival outcomes. These proteins may serve as potential biomarkers to help identify patients who could benefit most from this novel therapeutic approach. However, Sahin emphasized that while the results are promising, the study remains in the preclinical stage and requires further validation before being tested in human trials. Despite the early nature of the findings, the availability of leflunomide, an already approved drug, could accelerate the transition from laboratory research to clinical application. The team is optimistic that their dual-targeting strategy could offer a safer and more durable alternative to current treatments for TNBC. With continued research, this method might eventually provide a new option for patients facing one of the most challenging forms of breast cancer.