New Potential Therapeutic Target for Triple-Negative Breast Cancer

Researchers are reporting a potentially promising treatment to offer women with triple-negative breast cancer (TNBC), the most aggressive form of breast cancer. Researchers at Vanderbilt-Ingram Cancer Center recently published a study in the journal Science Translational Medicine that a targeted therapy for TNBC has been discovered, which may be significant since TNBC is the only type of breast cancer for which there are no approved targeted therapies.

The investigators have identified gene alterations that may explain why TNBC is resistant to most existing treatments. Even more notable, the new findings suggest that a targeted therapy currently in clinical development may prove to be beneficial.

Justin Balko, PhD, PharmD, and his colleagues report chemotherapy prior to surgery can eradicate TNBC in approximately 30% of patients. However, in other patients TNBC behaves in a manner resistant to chemotherapy and often metastasizes to distant sites in the body, at which point there is no proven cure. The researchers now have demonstrated that the JAK-STAT signaling pathway may play a role.

For this study, the investigators studied tumor samples from 111 patients treated at the Instituto Nacional de Enfermedades Neoplásicas in Lima, Perú. After sequencing the tumor samples, the authors found that the JAK2 gene was more frequently amplified in chemotherapy-treated TNBC than in tumors before treatment. The patients with JAK2 gene-amplified tumors also had a recurrence of their cancer sooner and were more likely to die within 20 months following surgery.

JAK2 appeared to increase in a limited number of patients where biopsies were collected at different times during treatment. The rate of JAK2 amplification in these tissues was similar to samples obtained after chemotherapy, suggesting that JAK2 plays a supporting role in drug resistance and cancer stem cell-like features.

In cell lines, the researchers first tested ruxolitinib (Jakafi), a general JAK inhibitor used to treat intermediate or high-risk myelofibrosis and patients with polycythemia vera; however, it did not block tumor formation in the JAK2-amplified cells. Next, they then turned to a JAK2-specific inhibitor now known as BSK805. It markedly reduced TNBC tumor growth in mice when paired with chemotherapy.

The researchers report that amplifications at 9p24 previously have been identified in breast cancer and other malignancies. However, they note that the genes within this locus causally associated with oncogenicity or tumor progression have been unknown. The current study found that the presence of JAK2/9p24 amplifications occurred at higher rates in chemotherapy-treated TNBCs than in untreated TNBCs or basal-like cancers, or in other breast cancer subtypes.