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

IκB kinase subunit epsilon (IKKε), a key component of NFκB and interferon signalling, has been identified as a breast cancer oncogene. Here we report that the IKKε/TBK1 axis plays a role in the initiation and progression of breast cancer osteolytic metastasis. Cancer-specific knockdown of IKKε in the human MDA-MB-231-BT cells and treatment with the verified IKKε/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  inhibition reduces the ability of breast cancer cells to grow, move and enhance osteoclastogenesis by engaging both IRF and NFκB signalling pathways. Thus, therapeutic targeting of the IKK  /TBK1 axis may be of value in the treatment of advanced triple negative breast cancer. of IKKε on the initiation, progression and metastasis of breast cancer. Using mouse models of syngeneic and human breast cancer, we showed that cancer-specific knockdown of IKK  in human MDA-MB-231 and administration of the IKKε/TBK1 inhibitor Amlexanox in immune-competent mice inoculated with syngeneic 4T1 cells inhibited skeletal tumour burden and reduced osteolytic bone damage. Administration of Amlexanox alone in mice reduced the growth of the syngeneic 4T1 breast cancer cells in the mammary fat pads and it significantly enhanced the anti-tumour and anti-metastatic properties of the FDA-approved Docetaxel[23] in mice after removal of the primary tumour. Collectively, these findings suggest that, due to the combined anti-tumour and anti-resorptive effects, IKKε inhibitors, alone and in combination with effects of cancer-specific inhibition and pharmacological inhibition of on skeletal tumour through intra-tibial injection of either MDA-MB-231 syngeneic 4T1 breast IKKε-shRNA tibia. micro–computed tomography Skeletal tumor growth was measured on 2D microCT images using Image J and results were expressed as a percentage of total metaphyseal area (4T1) or on H&E stained sections using the OsteoMeasure software at 10x magnification. compliment these studies and demonstrate that systemic administration of the pharmacological inhibitor of IKKε/TBK1 suppressed the ability of the syngeneic 4T1 breast cancer cells to home, grow and to enhance osteoclast number and osteolysis in mice. These data also expand on previous observations and suggest that the osteoprotective effect associated with IKKε/TBK1 inhibition is mediated not only by the effects on breast cancer cells but also by inhibition of IKKε/TBK1 in bone cells of the tumour microenvironment in the skeleton. Evidence for this comes from the in vivo observations that pharmacological inhibition of IKKε/TBK1 reduced osteoclast number and the in vitro data that showed that IKKε/TBK1 in either breast cancer cells or osteoclast precursors significantly reduced the ability to support osteoclast formation.