Gene Alterations May Explain Treatment Resistance of Triple-negative Breast Cancer

Gene Alterations May Explain Treatment Resistance of Triple-negative Breast Cancer
Gene Alterations May Explain Treatment Resistance of Triple-negative Breast Cancer

Amplification of the JAK2 gene frequently occurs in triple-negative breast cancer (TNBC), suggesting that specific inhibitors of JAK2 should be investigated in TNBC, a study published in Science Translational Medicine has shown.1

TNBC is the most aggressive form of breast cancer and currently has no approved targeted therapies.

Gene alterations identified in this study, led by investigators at Vanderbilt-Ingram Cancer Center (VICC) in Nashville, Tennessee, may explain why TNBC is resistant to most existing treatments. Further, the findings indicate that a targeted therapy currently in clinical development may prove beneficial.

Though chemotherapy eradicates TNBC for approximately 30% of patients, the remaining 70% often experience metastasis, for which there is no proven cure.

Many tumors, including breast cancer, are driven by the JAK-STAT gene-signaling pathway, which is critical to cell growth and survival. Some evidence has suggested that JAK2 may have a role in TNBC.

This study examined tumor samples from 111 patients who were treated at the Instituto Nacional de Enfermedades Neoplásicas (INEN), in Lima, Perú. The researchers sequenced the tumor samples and found that the JAK2 gene was amplified more frequently after chemotherapy than before the treatment. Cancer recurred sooner in patients with JAK2 gene-amplified tumors, and death within 20 months after surgery was more likely.

Together, these findings suggested that JAK2 may be a cause of drug resistance. Additionally, JAK2 was increased in some patients whose biopsies were collected at different times during treatment, and the rate of JAK2 amplification was similar to samples obtained after chemotherapy. These findings suggest that JAK2 has a role in drug resistance and cancer stem cell-like features.

Cell lines were used to test ruxolitinib, which is a general JAK inhibitor. However, it did not block tumor formation in the JAK2-amplified cells. So, the researchers tried BSK805, which is a JAK2-specific inhibitor, and it markedly reduced TNBC tumor growth in mice when paired with chemotherapy.

Since inhibiting JAK1 along with JAK2, as ruxolitinib does, was ineffective, this study suggests that specific JAK2 inhibitors may be a better approach.

Reference

1. Balko JM, Schwarz LJ, Luo N, et al. Triple-negative breast cancers with amplification of JAK2 at the 9p24 locus demonstrate JAK2-specific dependence. Sci Transl Med. 2016;8(334):334ra53. doi:0.1126/scitranslmed.aad3001.

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