A drug that treats rheumatoid arthritis, leflunomide, inhibited a metabolic pathway to kill tumors in breast cancer cells implanted in mice.1
Leflunomide is a pyrimidine synthesis inhibitor that is an immunosuppressor. The FDA approved its use for the treatment of rheumatoid arthritis and psoriatic arthritis.
Researchers discovered that leflunomide can inhibit a metabolic pathway that happens in tumors with mutations in PTEN. PTEN (phosphatase and tensin homolog) is a tumor suppressor gene, and mutations in this gene occur in many cancers.
Results from this research could offer a new treatment for aggressive cancers with few treatment options.
This study revealed how a mutation in PTEN affects a metabolic pathway in cancerous cells. PTEN-mutant cells required more glutamine, which in turn sped the production of DNA and caused unregulated tumor proliferation.
Because these cells became dependent on a glutamine flux through new synthesis of pyrimidine, this caused sensitivity to the inhibition of dihydroortate dehydrogenase. Leflunomide inhibits dehydroortate dehydrogenase and damages the DNA generated in the pathway.
When researchers administered leflunomide in vitro and in vivo, PTEN-mutant cells died and healthy cells remained alive.
The researchers transplanted human breast cancer cells into mice to test the efficiency of leflunomide. Administration of leflunomide resulted in significant reductions in tumor size.
These results suggest a possible therapy for aggressive, PTEN-mutant cancers. Many of these cancers, such as triple-negative breast cancer and glioblastoma, have few therapies.
1. Mathur D, Stratikopoulos E, Ozturk S, et al. PTEN regulates glutamine flux to pyrimidine synthesis and sensitivity to dihydroorotate dehydrogenase inhibition. Cancer Discov. 2017 Mar 2. doi: 10.1158/2159-8290.CD-16-0612 [Epub ahead of print]