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

Ryan T. Bishop, Silvia Marino, Danielle de Ridder, Richard J Allen, Diane V Lefley, Andrew H. Sims, Ning Wang, Penelope D Ottewell, Aymen I. Idris

Research output: Contribution to journalArticlepeer-review

Abstract

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 IKKƐ 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 IKKƐ/TBK1 axis may be of value in the treatment of advanced triple negative breast cancer.
Original languageEnglish
JournalCancer letters
DOIs
Publication statusPublished - 18 Feb 2019

Keywords

  • IKKƐ
  • NFkB
  • breast cancer
  • combination treatment
  • bone metastasis
  • osteolysis
  • osteoclast
  • osteoblast
  • bone

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