Researchers found that blocking LOX and then DHODH slowed chemotherapy-resistant triple-negative breast cancer in laboratory and animal models. The approach is promising, but it has not yet been tested or approved for people.
Early laboratory research finds that blocking two survival systems may slow hard-to-treat tumors without chemotherapy.
Triple-negative breast cancer (TNBC) is one of the most difficult forms of breast cancer to treat. It does not have the three common targets, estrogen receptors, progesterone receptors, or HER2, that many breast cancer medicines are designed to attack. Because of this, chemotherapy is often a main treatment option.
Chemotherapy can work well at first. But TNBC cells can adapt, survive, and begin growing again. This is called treatment resistance.
A new study from researchers at MUSC Hollings Cancer Center points to a possible new way to fight that resistance. The approach uses a “one-two punch”: first weaken cancer cells by blocking a protein called LOX, then block the backup system the cells use to stay alive.
The results are encouraging, but there is an important catch: this research was done in lab models and in mice, including models made from patient tumors. It has not yet been tested as a treatment in people.
MUSC Ozge Saatci, Ph.D., Ozgur Sahin, Ph.D., and Burge Ulukan, Ph.D., researchers. Photo by Clif Rhodes.
What did the new study find?
The study, published in Cell Reports Medicine, focused on a protein called lysyl oxidase, or LOX.
Scientists have long known that LOX can change the tissue around a tumor. It can make that tissue stiffer, which may help cancer spread and can make it harder for medicines to reach the tumor.
But the new research found that LOX also has an important job inside TNBC cells.
Inside the cancer cell, LOX helps support energy production and keeps mitochondria working. Mitochondria are often called the “power plants” of cells because they help make energy. LOX also helps cancer cells handle stress and avoid damage.
When the researchers blocked LOX, the cancer cells became weaker. They had trouble making energy, maintaining healthy mitochondria, and protecting themselves from harmful molecules.
That was the first punch.
The second punch: blocking a backup defense
Cancer cells are very good at adapting. When LOX was blocked, the TNBC cells leaned more heavily on another protein called DHODH.
DHODH helps cells make building blocks for DNA and RNA. It also helps protect mitochondria from a type of damage called lipid peroxidation. This happens when fats in a cell membrane are damaged by unstable molecules.
The researchers found that blocking both LOX and DHODH overwhelmed the cancer cells. The cells then went through a form of cell death called ferroptosis.
Ferroptosis is different from the better-known process of apoptosis, or programmed cell death. It happens when iron-related damage builds up in the fatty parts of a cell until the cell can no longer survive.
Earlier research has helped explain why DHODH matters. A 2021 study in Nature found that DHODH can act as a defense against ferroptosis in the mitochondria of cancer cells. More recent TNBC research has also shown that DHODH can help these cells avoid ferroptosis.
This new study connects those ideas: blocking LOX creates a weak spot, and blocking DHODH removes a key backup defense.
Which medicines were used?
The researchers paired an experimental LOX-blocking drug, called LXG6403, with leflunomide.
Leflunomide is already approved by the U.S. Food and Drug Administration for certain autoimmune conditions. In the body, it blocks DHODH.
Using an already approved medicine can be helpful in research because doctors already know a great deal about its dosing and side effects in its approved use. But that does not mean leflunomide is approved or proven for triple-negative breast cancer.
In several preclinical TNBC models, the drug combination slowed tumor growth. The researchers reported that it worked without major weight loss or signs of kidney or liver toxicity in the models they studied. The combination also performed better than pairing the LOX blocker with a standard chemotherapy drug in those experiments.
Why LOX is an especially interesting target
This is not the first time scientists have connected LOX to treatment resistance in TNBC.
In a 2020 study, several of the same researchers found that high LOX activity could make TNBC tumors more resistant to chemotherapy. In that earlier work, LOX helped change the material around tumors, limiting drug delivery and turning on cell-survival signals.
The new research adds another layer. It suggests that LOX may also help cancer cells survive from the inside by controlling metabolism, energy production, and stress defenses.
Together, the findings suggest that LOX may be doing two harmful jobs in TNBC:
It may help create a tumor environment that is harder for medicines to enter.
It may help cancer cells stay energized and resist cell death.
That makes LOX a promising target for future research.
Could this help patients someday?
Possibly, but more research is needed.
The researchers also looked at tumor samples from people with TNBC. Tumors with higher LOX levels showed greater activity in energy and survival pathways seen in the laboratory. Patients whose tumors had high levels of both LOX and DHODH had poorer survival.
This raises the possibility that LOX and DHODH could someday be used as biomarkers. Biomarkers are features in a tumor that may help doctors predict how a cancer will behave or which treatments may work best.
Before this approach can be used in patients, researchers will need to complete more safety studies and then test it in clinical trials. They will need to learn the right dose, which patients may benefit, whether the combination is safe over time, and how it compares with current treatments.
The study authors are working on a newer version of their LOX inhibitor with collaborators at the University of South Carolina.
What this means for people with TNBC today
This study does not change the current standard of care for triple-negative breast cancer. No one should start, stop, or change treatment based on these findings without talking with their cancer care team.
Still, the research offers a hopeful direction. Instead of only trying to kill cancer cells with chemotherapy, scientists are looking for ways to expose the survival systems cancer cells depend on and then block them.
For people facing TNBC, that could one day lead to more targeted treatments, fewer chemotherapy-related side effects, and better options when cancer becomes resistant to treatment.
Key Takeaways
Researchers found that the protein LOX helps TNBC cells make energy, protect their mitochondria, and survive stress.
Blocking LOX made cancer cells depend more on DHODH, another survival pathway.
Blocking both LOX and DHODH triggered ferroptosis and slowed tumor growth in preclinical models.
The approach used an experimental LOX inhibitor and leflunomide, a medicine already approved for other conditions.
This is promising early research, but it has not yet been tested as a treatment in people with TNBC.
FAQ's
What is the new treatment being studied for triple-negative breast cancer?
Researchers are studying a two-drug approach for triple-negative breast cancer (TNBC) that has become resistant to chemotherapy. The first drug blocks a protein called LOX. This weakens the cancer cell by disrupting its energy supply and stress defenses. The second drug blocks DHODH, a backup pathway the cancer cell uses to survive.
This approach is still in the early stages of research. It is not an approved treatment for TNBC.
What are LOX and DHODH?
LOX, short for lysyl oxidase, is a protein that can help tumors in two ways. Outside cancer cells, it can make the tissue around a tumor stiffer, which may make it harder for drugs to reach the cancer. Inside cancer cells, the new study found that LOX helps the cells make energy, protect their mitochondria, and handle stress.
DHODH is another protein found in mitochondria, the parts of cells that help produce energy. It helps cells make materials needed for DNA and RNA. It also helps protect cancer cells from a type of damage that can lead to ferroptosis.
In this study, blocking LOX made TNBC cells rely more heavily on DHODH. Blocking DHODH at that point removed an important backup defense.
Is leflunomide approved to treat breast cancer?
No. Leflunomide is not approved by the U.S. Food and Drug Administration to treat breast cancer. It is approved to treat adults with active rheumatoid arthritis. In this study, researchers used it because it blocks DHODH, a protein that became important to cancer cells after LOX was blocked.
Doctors sometimes study approved medicines for new uses. This is called drug repurposing. However, a medicine being approved for one condition does not mean it is safe or effective for another. Leflunomide can have serious side effects and should only be used under the guidance of a qualified health care professional.
Has this two-drug approach been tested in people?
Not yet. The LOX inhibitor plus leflunomide combination was tested in cancer cells and in preclinical models, including models created from patient tumors. These studies found that the combination slowed tumor growth without major signs of kidney or liver toxicity in the models studied.
Sources: Saatci et al., “Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC,” Cell Reports Medicine (2026); MUSC Hollings Cancer Center; Saatci et al., Nature Communications (2020); Mao et al., Nature (2021); and research on DHODH-mediated ferroptosis resistance in TNBC published in Cell Death & Disease (2025).
