Approximately 15,000 Australian women are diagnosed with breast cancer annually and around 30% of breast cancer patients will develop metastases to the lung, liver, bone or brain, the main cause of mortality in breast cancer patients. Once brain metastases are established, prognosis is extremely poor, with a median survival of ~4-6 months. Current systemic and targeted therapies extend the life of patients but their limited efficacy against brain-metastatic triple negative (ER-/PR-/HER2-) breast tumours is contributing to the increased incidence of patients developing brain metastases. Recent in vitro and animal studies have shown that first-generation histone deacetylases (HDAC) inhibitors such as suberanilohydroxamic acid (SAHA) enhance the radiosensitivity of brain metastatic breast cancer and reduce brain metastasis in experimental metastasis models.
Here, we report on the inhibitory and radiosensitising properties of two novel HDAC inhibitors (SB939 and 1179.4b) against mouse (4T1Br4) and human (MDA-MB-231Br) brain-metastatic triple negative breast cancer in vitro and in vivo. Specifically, we demonstrate that SB939 and 1179.4b inhibit the growth of 4T1Br4 and MDA-MB-231Br cells more efficiently that SAHA in standard in vitro proliferation and colony forming assays. These responses are associated with increased histone H3 acetylation. Moreover, SB939 and 1179.4b sensitise 4T1Br4 and MDA-MB-231Br cells to radiation, as evidenced by reduced colony forming efficiency and induction of γ-H2AX foci, a marker of DNA double strand breaks. In vivo, daily administration of SB939 or 1179.4b significantly inhibited primary tumour growth and reduced metastatic burden in the 4T1Br4 model. Taken together, our results demonstrate the superior potency of SB939 and 1179.4b against brain-metastatic triple negative breast cancer and warrant further investigation in patients.