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Radiation therapy remains a cornerstone of lung cancer treatment, yet its long-term effectiveness is often undermined by a persistent challenge: tumors adapt and become resistant. Understanding, and overcoming, this resistance is a major priority in oncology.

A new study from researchers at The University of Texas MD Anderson Cancer Center, published in Cancer Research, identifies a metabolic mechanism that allows lung cancer cells to evade radiation-induced death and proposes a clinically actionable strategy to counter it.

A hidden driver of resistance

Radiotherapy works by damaging cancer cells in multiple ways, including triggering ferroptosis—an iron-dependent form of cell death driven by oxidative stress. However, many tumors develop the ability to suppress this process, allowing them to survive treatment.

The new study pinpoints a key player in this resistance: the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). Researchers found that radiation exposure increases DHODH activity in lung cancer cells, enabling them to withstand ferroptosis and continue growing.

“This is an important finding because of the immediate translational opportunity,” said Boyi Gan, PhD, senior author of the study. “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.”

A metabolic shield against cell death

DHODH is best known for its role in nucleotide synthesis, helping cells produce the building blocks needed for DNA repair and replication. But the study highlights an additional function that is particularly relevant in cancer.

The enzyme also supports the production of ubiquinol, a molecule that protects cells from oxidative damage. In the context of radiation therapy, this acts as a shield, preventing the lipid damage required to trigger ferroptosis.

By simultaneously promoting DNA repair and suppressing ferroptosis, DHODH enables cancer cells to survive what would otherwise be lethal radiation-induced stress.

Repurposing an existing drug

Rather than developing a new inhibitor from scratch, the researchers turned to leflunomide—an FDA-approved drug currently used to treat rheumatoid arthritis, which is known to inhibit DHODH.

In preclinical models, blocking DHODH alone modestly increased sensitivity to radiation. However, the most striking results emerged when the team combined three treatment modalities: radiation therapy, immune checkpoint blockade, and DHODH inhibition.

Radiation plus immunotherapy alone was insufficient to control tumor growth. But when leflunomide was added, the combination restored ferroptosis and led to a marked reduction in tumor progression.

“DHODH inhibition alone had some effect on sensitization to radiation therapy, but it was really this triple combination that had a marked effect,” Gan said.

Leveraging the immune response

A key aspect of the strategy lies in its interaction with the immune system. Immunotherapy, specifically anti–PD-1 checkpoint blockade, stimulates the production of interferon-gamma (IFN-γ), a signaling molecule that can enhance ferroptosis.

However, in resistant tumors, this signal alone is not enough to overcome the protective effects of DHODH. By inhibiting the enzyme, the researchers effectively remove this metabolic barrier, allowing IFN-γ–driven ferroptosis to proceed.

The result is a coordinated therapeutic effect in which radiation induces stress, immunotherapy amplifies cell death signals, and DHODH inhibition prevents tumor cells from escaping.

Toward clinical translation

One of the most compelling aspects of the study is its translational potential. Leflunomide is already widely used in clinical practice, with a well-characterized safety profile, potentially accelerating its evaluation in oncology settings.

“These findings provide a good rationale for testing this combination in clinical studies,” Gan said in a press release.

If validated in patients, this approach could offer a new strategy for overcoming resistance not only in lung cancer but potentially in other solid tumors treated with radiotherapy.

A broader shift in cancer therapy

The findings also reflect a broader trend in cancer research: targeting metabolic pathways that enable tumor survival under stress. While traditional therapies focus on directly damaging cancer cells, emerging approaches aim to disrupt the adaptive mechanisms that allow tumors to recover.

By linking metabolism, immune signaling, and cell death pathways, the study provides a more integrated view of how resistance develops—and how it can be reversed.

Although the results are based on preclinical models, they offer a clear path forward. Future clinical trials will be needed to determine whether the triple combination strategy can improve outcomes in patients with radioresistant lung cancer.

More broadly, the work highlights the importance of identifying “druggable” vulnerabilities within resistance pathways, especially those that can be targeted with existing therapies.

In this case, a drug originally developed for autoimmune disease may help solve one of the most persistent challenges in cancer treatment: restoring the effectiveness of radiation therapy when it begins to fail.

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