Novel Target May Improve Treatment Outcomes in Triple-Negative Breast Cancer

A metabolic vulnerability in triple-negative breast cancer (TNBC) cells was identified that could be harnessed to circumvent chemotherapy resistance.

TNBC is a difficult-to-treat and aggressive form of breast cancer that lacks targetable receptors found in other breast cancer forms. Only 30% of patients with TNBC achieve a pathologic complete response following chemotherapy, of which, most frequently relapse shortly after.

In a study published in Cancer Discovery, investigators demonstrated that chemotherapy reprograms TNBC to increase the production of the pyrimidine nucleotides. This process heightens the cells’ DNA repair abilities, resulting in greater resistance to chemotherapies that occur by damaging the DNA of rapidly dividing cells.

“This actually makes sense if you think about it, because if a tumor cell is going to repair DNA and therefore evade the death-inducing effects of chemotherapy, the only way they can really do that is by rebuilding DNA, and the only way to rebuild DNA is to make more nucleotides,” said investigator Alex Toker.

The investigators hypothesized that blocking the pyrimidine synthesis pathway in TNBC cells would hinder their DNA repair abilities, increasing their susceptibility to the DNA-damaging effects of chemotherapy.

In the lab, investigators exposed TNBC cells to drug combination doxorubicin and leflunomide. Leflunomide is a known inhibitor of dihydroorotate dehydrogenase, a crucial enzyme in the biochemical reactions that generate pyrimidines.

“One of the major reasons we chose leflunomide is because we wanted a rapid path to clinical impact, and leflunomide is already FDA-approved and widely used to treat autoimmune diseases such as rheumatoid arthritis,” Toker said.

The results of the study showed that leflunomide blocked the increase of pyrimidine nucleotides in TNBC cells, which impaired their ability to repair DNA damage by doxorubicin and resulted in the increase in cancer cell death.

The experiment was then repeated in mice with transplanted human TNBC cells.

“We found that treating the mice with doxorubicin or leflunomide alone only slowed tumor growth, but that a combination therapy involving both drugs resulted in significant tumor regression,” Toker said.

The authors noted that the combination regimen did not cause weight loss or gain in the mice, indicating that the therapy may be reasonably well-tolerated in humans.

“One of the things we would like to do is develop clinical trials in patients with this combination strategy, whether it be with leflunomide or some other drugs that are coming online that might have better pharmacological properties in patients,” Toker said.

For now, the investigators are moving forward with plans to examine the molecular basis of increased pyrimidine biosynthesis in TNBC cells.

“There is something about this pathway in triple-negative breast cancer that is especially important,” Toker said. “We don’t know what the genetic basis underlying it is, but it’s something we would really like to find out.”