Blocking DHODH Helps Triple Combination Overcome Radiotherapy Resistance in Lung Cancer

Researchers from MD Anderson identified DHODH as a key metabolic driver of radiotherapy resistance in lung cancer. Radiation increased DHODH activity, enabling tumor cells to suppress ferroptosis and support DNA repair. While DHODH inhibition alone had a limited effect, adding leflunomide to radiotherapy plus anti-PD-1 therapy restored ferroptosis and overcame resistance.

Published in Cancer Research, a new preclinical study from The University of Texas MD Anderson Cancer Center uncovered a metabolic mechanism that allows tumors to escape radiotherapy and suggested that an already approved drug may help dismantle it.

Led by Boyi Gan, Ph.D., professor of Experimental Radiation Oncology, the researchers discovered the mitochondrial enzyme dihydroorotate dehydrogenase, DHODH, as a key driver of radioresistance in lung cancer. The work shows that radiation induces DHODH expression in a CREB-dependent manner, and that both radiation exposure and acquired radioresistant states are associated with elevated DHODH activity. In effect, the enzyme helps tumors survive one of radiotherapy’s less appreciated lethal effects: ferroptosis.

How DHODH Shields Lung Cancer Cells From Ferroptosis

Ferroptosis is an iron-dependent form of cell death triggered by oxidative damage to cellular membranes. Radiation not only injures DNA, but also generates the kind of lipid damage that pushes cells into ferroptosis. But in these experiments, lung cancer cells countered that pressure by increasing DHODH. 

That mattered for two reasons. First, DHODH helped generate ubiquinol, a mitochondrial lipid antioxidant that suppresses ferroptosis. Second, because the enzyme is central to de novo pyrimidine synthesis, it also supported the production of building blocks needed for DNA repair. Together, those two functions gave cancer cells a powerful survival advantage: less ferroptotic damage, more capacity to recover from radiation-induced injury.

“This is an important finding because of the immediate translational opportunity,” Gan said. “By understanding how DHODH is preventing cell death in radioresistant cancer cells, we were able to develop a strategy to overcome radiation therapy resistance in tumor models.”

That strategy centered on leflunomide, an FDA-approved drug used for rheumatoid arthritis and a known DHODH inhibitor. The appeal is obvious. Rather than designing a new compound from scratch, the researchers tested whether an existing agent could expose a metabolic vulnerability already present in resistant tumors.

On its own, however, DHODH inhibition was not enough. The abstract makes that point clearly: DHODH inhibition alone had limited therapeutic effect in preclinical models. The more striking results emerged when the investigators combined three elements, radiotherapy, anti-PD-1 immunotherapy, and leflunomide.

The biology behind that combination is elegant. Anti-PD-1 therapy increased interferon-gamma, IFN-γ, a cytokine that can further promote ferroptosis. When DHODH was simultaneously blocked, tumor cells lost a crucial defense against ferroptotic death. In that setting, radiotherapy became more effective again, and previously resistant tumors responded in preclinical models.

“DHODH inhibition alone had some effect on sensitization to radiation therapy, but it was really this triple combination that had a marked effect on the lung cancer models,” Gan said. “These findings provide a good rationale for testing this combination in clinical studies.”

Why This Mechanism May Matter Beyond Lung Cancer

The study is important not only because it identifies DHODH as a metabolic regulator of radioresistance, but also because it reframes resistance as something more than a DNA repair problem. It places ferroptosis defense at the center of the story. That shift could matter well beyond lung cancer, especially in solid tumors where radiotherapy remains standard but durable responses are often undermined by adaptive survival programs.

These are preclinical data, and the benefit of combining radiotherapy, immune checkpoint blockade, and DHODH inhibition still needs to be tested in patients. Leflunomide also carries its own safety considerations, and translating such a regimen into the clinic will require careful work on dose, sequence, and tolerability.