ACY-1215 is a novel and selective oral inhibitor of HDAC6 currently in Phase I clinical trials in combination with bortezomib or lenalidomide in relapsed/refractory multiple myeloma. Inhibitors of HDAC6 have demonstrated anti-cancer proliferative activity in various cancer types, including Her2+ breast cancer. Blocking HDAC6 activity has been shown to cause Her2+ breast cancer cell growth inhibition through various mechanisms, including destabilization of Her2 mRNA and protein. In the present work, the impact of HDAC6 inhibition has been investigated on Her2+ breast cancer cell growth and cell migration using HDAC6 inhibitor alone or in combination with either a Her2 inhibitor (lapatinib) or a PI3K inhibitor (GDC-0941, IPI-145 and CAL-101).
Anti-tumor activity of ACY-1215 was investigated using a panel of nearly 100 human tumor cell lines derived from the major cancer types and Her2+ breast cancer cells were among the most sensitive cells to ACY-1215. Combinations of ACY-1215 with either the Her2 inhibitor lapatinib or PI3K inhibitor GDC-0941 demonstrated synergistic cytotoxicity against these cancer cells. To illustrate the effects are due to HDAC6 inhibition, we used a highly HDAC6 selective inhibitor ACY-775, which has greater than 1,500 fold of selectivity against HDAC6 over Class I HDACs (HDAC1, 2 and 3), in our experiments. ACY-775 is able to sensitize Her2+ breast cancer cells MDA-MB-453 and BT-474 to lapatinib, and PI3K inhibitors (IPI-145, GDC-0941 and CAL-101). ACY-775 also blocks cancer cell migration in the presence of absence of epidermal growth factor (EGF). In agreement with the proposed mechanism of HDAC6 mediated Her2+ breast cancer cell death, ACY-1215 treatment correlated with decrease of Her2 protein, p-EGFR and p-AKT in a Her2+ breast cancer cell line MDA-MB-453.
By taking advantage of our highly selective HDAC6 inhibitor ACY-775, we have shown growth and migration suppressive activities by HDAC6 inhibition in Her2+ breast cancer cells. These findings suggest selection of metastatic Her2+ breast cancer for further in vitro and in vivo validation and mechanism of action studies with ACY-1215 in combination with novel and approved standard of care therapeutics for breast cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B280.
Citation Format: Min Yang, David Tamang, Simon Jones. Histone deacetylase (HDAC) 6 inhibition potentiates the cytotoxicity of lapatinib and PI3K inhibitors on Her2+ breast cancer cell lines. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B280.