A weakness could reduce chemotherapy reliance in triple-negative breast cancer

Triple-negative breast cancer (TNBC) lacks three common treatment targets, leaving chemotherapy as a mainstay despite its serious side effects and the frequent development of resistance. Researchers identified an unexpected role for lysyl oxidase (LOX) inside TNBC cells: it supports energy production, keeps mitochondria functioning and helps cells withstand stress. Blocking LOX disrupts several survival systems at once, but cancer cells compensate by relying more heavily on a backup defense controlled by DHODH. This adaptation creates a vulnerability that can be targeted in turn.

In laboratory tests and several preclinical models, including tumors derived from patients whose cancers resisted chemotherapy, researchers paired an experimental LOX inhibitor with leflunomide, an FDA-approved drug that blocks DHODH. The combination triggered ferroptosis, a form of cell death caused by toxic damage, and significantly suppressed tumor growth. It outperformed a LOX-inhibitor and chemotherapy combination, without major weight loss or signs of liver or kidney toxicity in the models tested. Patient tumor data also linked high LOX and DHODH activity with poorer survival, suggesting the proteins might help identify people who could benefit. The approach is not ready for patients: its safety and effectiveness in people remain untested. But repurposing an approved drug could ease the path to clinical studies, and the strategy may eventually offer a way to reduce reliance on chemotherapy.