New vulnerability in aggressive breast cancer provides treatment target

Researchers from the Cancer Center at Beth Israel Deaconess Medical Center (BIDMC), Massachusetts, US, have discovered a vulnerability that could provide a new strategy to combat triple-negative breast cancer (TNBC).

Currently, physicians currently have no targeted treatment options available for women diagnosed with the aggressive form of breast cancer, leaving standard-of-care chemotherapies as the first defence against the disease.

However, most women with TNBC do not respond to these chemotherapies, while those who do often develop resistance to the drugs.

Corresponding author of the study Dr Alex Toker, chief of the Division of Signal Transduction in the Department of Medicine and Pathology and the Cancer Center at BIDMC, said: “Given the complete lack of any targeted therapies specific to triple-negative breast cancer, we started thinking about how we could find other vulnerabilities in tumour cells.

“If we could find such vulnerabilities, we could develop strategies to exploit them, perhaps with already FDA-approved drugs that could be used in combination with existing cancer drugs.”

Scientists don't know what initiates or drives the development of TNBC tumours. However, the BIDMC researchers found that the cancer cells increase production of nucleotides called pyrimidines when exposed to standard chemotherapy.

Since pyrimidines are a crucial ingredient in DNA, they deduced that its increased production - known as biosynthesis - is an adaptive response promoting resistance to DNA-damaging chemotherapies.

Dr Toker said that chemotherapy reprograms this pyrimidine-biosynthetic pathway to “crank up production of these nucleotides”. He explained that the researchers thought that if they could inhibit this increase, they might be able to “restore the chemotherapeutic benefit of standard-of-care drugs”.

In order to test the theory, the scientists treated TNBC cells with a cancer-killing drug called doxorubicin. The cancer cells did indeed increase production of pyrimidine nucleotides, as expected.

The researchers then treated TNBC cells with a combination of a standard-of-care chemotherapy called doxorubicin and leflunomide, a drug known to block the pyrimidine biosynthetic pathway that is already an FDA-approved treatment for rheumatoid arthritis.

Following that treatment, TNBC cells responded as expected. In mice, there was significant tumour regression with the combination therapy.

Other experiments revealed that using either of the drugs alone had a minimal impact on TNBC cells, while the combination therapy had no impact on the other breast cancer subtypes driven by estrogen, progesterone or HER2.ADNFCR-2094-ID-801833123-ADNFCR