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MD Anderson Research News
In a preclinical study published today in Cancer Research, a journal of the American Association for Cancer Research, researchers at The University of Texas MD Anderson Cancer Center identified one way lung cancer becomes resistant to radiation therapy and then developed a strategy to overcome this challenge.
| These results show how mitochondrial enzyme dihydroorotate dehydrogenase contributes to radiation therapy resistance |
| Researchers were able to overcome the resistance with a triple combination therapy including leflunomide, an FDA-approved drug used for rheumatoid arthritis |
Led by Boyi Gan, Ph.D., professor of Experimental Radiation Oncology, researchers discovered that the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) can protect cancer cells from ferroptosis – an iron-dependent form of cell death triggered by radiation – thereby contributing to radiation therapy resistance in lung cancer. In preclinical models, the researchers were able to overcome this resistance by inhibiting DHODH with leflunomide, an arthritis medication already approved by the Food and Drug Administration (FDA).
“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.”
Why is the discovery of how DHODH helps tumors evade radiation significant?
Radiation therapy is one of the standard treatments for lung cancer, but patients often develop resistance to it. How exactly that resistance forms is not completely understood.
Radiation therapy eliminates cancer cells in multiple ways. It can damage the DNA inside the cell so severely that the cell can no longer repair itself, triggering apoptosis – a programmed form of cell death that allows the body to safely eliminate damaged cells. Radiation also can injure cell membranes, leading to another type of cell death known as ferroptosis.
In this study, the researchers found one way that lung cancer cells fight back against ferroptosis is by increasing production of DHODH, an enzyme important for creating the building blocks of RNA and DNA. Increasing DHODH levels not only helped the cells assemble more of the building blocks needed to repair DNA, but it also produced a molecule known as ubiquinol that blocked the ferroptosis process.
This finding is significant because it led to the hypothesis that inhibiting DHODH could help overcome this resistance, and there is already an approved DHODH inhibitor available.
How does leflunomide help overcome radiation resistance?
In this study, the researchers developed a triple combination therapy.
Radiation is delivered, followed by immunotherapy (anti-PD-1 immune checkpoint blockade). This combination alone failed to stop tumor growth in the preclinical models. However, immunotherapy led to an upregulation of interferon-gamma (IFN-γ), which also helps promote ferroptosis. When the DHODH inhibitor leflunomide was added to the combination, the cells were no longer able to resist ferroptosis, and the tumors once again responded to radiotherapy.
“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.”
***This study was funded by the National Institutes of Health (NIH), the Cancer Prevention and Research Institute of Texas (CPRIT), The University of Texas at Austin and UT MD Anderson through the Collaborative Accelerator for Transformative Research Endeavors grant, and The N.G. and Helen T. Hawkins Distinguished Professorship for Cancer Research. A full list of authors and their disclosures can be fo
