Pharmacological inhibition of the IKKε/TBK-1 axis potentiates the anti-tumour and anti-metastatic effects of Docetaxel in mouse models of breast cancer

I kappa B kinase subunit epsilon (IKK epsilon), a key component of NF kappa B and interferon signalling, has been identified as a breast cancer oncogene. Here we report that the IKK epsilon/TBK1 axis plays a role in the initiation and progression of breast cancer osteolytic metastasis. Cancer-specific knockdown of IKK epsilon in the human MDA-MB-231-BT cells and treatment with the verified IKK epsilon/TBK1 inhibitor Amlexanox reduced skeletal tumour growth and osteolysis in mice. In addition, combined administration of Amlexanox with Docetaxel reduced mammary tumour growth of syngeneic 4T1 cells, inhibited metastases and improved survival in mice after removal of the primary tumour. Functional and mechanistic studies in breast cancer cells, osteoclasts and osteoblasts revealed that IKK epsilon inhibition reduces the ability of breast cancer cells to grow, move and enhance osteoclastogenesis by engaging both IRF and NF kappa B signalling pathways. Thus, therapeutic targeting of the IKK epsilon/TBK1 axis may be of value in the treatment of advanced triple negative breast cancer.