Triple-negative breast cancer, or TNBC, presents numerous treatment challenges. Compared with other forms of breast cancer, it’s more likely to have spread at the time of diagnosis and is more likely to recur, largely because it becomes resistant to chemotherapy.

Researchers at Roswell Park Comprehensive Cancer Center have identified a previously unknown cause of resistance to doxorubicin, a mainstay of treatment for this aggressive, fast-growing breast cancer subtype. The team’s new study in Scientific Reports points to a new strategy for overcoming this resistance to treatment, using drugs known as IMPDH2 inhibitors.

Anna Bianchi-Smiraglia, PhD, led work that has identified a possible strategy for overcoming aggressive triple-negative breast cancers that do not respond to standard chemotherapy.

A team led by senior author Anna Bianchi-Smiraglia, PhD, Assistant Professor of Oncology, Department of Cell Stress Biology, discovered that inosine monophosphate dehydrogenase 2 (IMPDH2) helps protect cancer cells from doxorubicin, and that IMPDH2-inhibitor drugs already on the market can target that protection.

IMPDH2 is a metabolic enzyme that assists in the production of the nucleotide guanine triphosphate (GTP), which previously has been shown to help cancer metastasize, or spread. High expression of IMPDH2 has been linked to chemotherapy resistance and poor survival in several types of cancer, including osteosarcoma, glioblastoma and colorectal cancer. However, until now it was not clear whether the same held true for TNBC.

Through their analysis of publicly available datasets, the research team found that TNBC patients who had a high expression of IMPDH2 had a worse overall prognosis, including lower recurrence-free survival after receiving chemotherapy before or after surgery. This finding suggests that IMPDH2 levels in TNBC patients could be used predict both their response to treatment and their prognosis or expected clinical outcomes.

Then, through preclinical studies involving doxorubicin-resistant models of TNBC, the team discovered that IMPDH2 levels actually increased following multiple rounds of treatment with increasing doses of doxorubicin. However, while this helped the cells become more resistant to doxorubicin, it also made them far more vulnerable to the IMPDH2-inhibitor drugs ribavirin (RBV) and mycophenolic acid (MPA), which reduced the growth of chemo-resistant tumors. Both ribavirin and mycophenolic acid are already FDA-approved for non-cancer-related conditions.

While further research will be needed to validate and support the team’s findings, the work could pave the way to a new treatment strategy.

“Our data suggest that elevated levels of IMPDH2 and its downstream product GTP play a role in chemotherapy resistance that is either present before treatment or that occurs in response to treatment,” says Dr. Bianchi-Smiraglia, Assistant Professor of Oncology in Roswell Park’s Department of Cell Stress Biology. “However, this increased reliance on the IMPDH2/GTP pathways makes the cells exquisitely sensitive to IMPDH2 inhibition. This novel metabolic vulnerability could be the Achilles heel of chemo-resistant cells and represents a novel therapeutic target for therapy-resistant TNBC.”

TNBC represents between 10-15% of all breast cancer subtypes and is more common in Black people, those under 40 and those who have a mutation of the BRCA gene. At the time of relapse, five-year survival stands at only 12%.

Tatiane Da Silva Fernandes, PhD, co-led the work as first author during her time as a predoctoral research affiliate in Dr. Bianchi-Smiraglia’s lab at Roswell Park, and Spencer Rosario, PhD, a faculty member in the Department of Biostatistics and Bioinformatics, is a corresponding author. The work was funded in part by grants from the National Cancer Institute (project numbers CA248018 and P30CA16056) and the Roswell Park Alliance Foundation.

The work was funded in part by grants from the National Cancer Institute (project numbers CA248018 and P30CA16056) and the Roswell Park Alliance Foundation.

Source: Roswell Park Team