Preclinical TNBC study tests a LOX-DHODH drug pairing

Inside the laboratories of MUSC Hollings Cancer Center, researchers found a new way to pressure triple-negative breast cancer cells: weaken them first, then block the escape route they depend on. The strategy combined an experimental drug that inhibits lysyl oxidase, or LOX, with leflunomide, an FDA-approved drug, and significantly blocked tumor growth in several preclinical models without chemotherapy.

Triple-negative breast cancer, known as TNBC, lacks three common targets used to treat other breast cancers. Chemotherapy remains a primary treatment, but the cancer can adapt after an initial response. The team led by Dr. Ozgur Sahin, with postdoctoral fellows Dr. Burge Ulukan and Dr. Ozge Saatci, studied why these cells survive.

LOX was already known for reshaping the tissue around tumors. The MUSC researchers found that it also works inside TNBC cells, supporting energy production, maintaining healthy mitochondria and protecting the cells from stress. Blocking LOX disrupted those systems and left the cancer cells more vulnerable.

The weakened cells then leaned more heavily on DHODH, a protein controlling a backup defense against ferroptosis — a form of cell death caused by toxic damage inside the cell. Blocking both LOX and DHODH caused damaging molecules to build up until the cancer cells underwent ferroptosis. Leflunomide supplied the second blockade.

Concretely, the result offers a possible non-chemotherapy strategy for tumors that have become chemotherapy-resistant, including tumors represented in patient-derived preclinical models. The combination caused no major weight loss or signs of kidney or liver toxicity in those models and outperformed the LOX inhibitor paired with standard chemotherapy. But these are laboratory and preclinical findings; the study does not establish that the approach works in patients.