Zhou, Jiabao, Down, Jennifer M, George, Christopher N, Murphy, Jessica, Lefley, Diane V, Tulotta, Claudia, Alsharif, Marwa A, Leach, Michael ORCID: https://orcid.org/0000-0002-9859-1325 and Ottewell, Penelope D (2022) Novel methods of targeting IL-1 signalling for the treatment of breast cancer bone metastasis. Cancers, 14 (19):4816. ISSN 2072-6694 (Online) (doi:10.3390/cancers14194816)

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Abstract

Breast cancer bone metastasis is currently incurable. Evidence suggests that inhibiting IL-1 signalling with the IL1R antagonist, Anakinra, or the IL1β antibody, Canakinumab, prevents metastasis and almost eliminates breast cancer growth in the bone. However, these drugs increase primary tumour growth. We, therefore, investigated whether targeting other members of the IL-1 pathway (Caspase-1, IL1β or IRAK1) could reduce bone metastases without increasing tumour growth outside of the bone. Inhibition of IL-1 via MLX01 (IL1β secretion inhibitor), VRT043198/VX765 (Caspase-1 inhibitor), Pacritinib (IRAK1 inhibitor) or Anakinra (IL1R antagonist) on tumour cell viability, migration and invasion were assessed in mouse mammary E0771 and Py8119 cells in vitro and on primary tumour growth, spontaneous metastasis and metastatic outgrowth in vivo. In vitro, Inhibition of IL-1 signalling by MLX01, VRT043198 and Anakinra reduced migration of E0771 and Py8119 cells and reversed tumour-derived IL1β induced-increased invasion and migration towards bone cells. In vivo, VX765 and Anakinra significantly reduced spontaneous metastasis and metastatic outgrowth in the bone, whereas MLX01 reduced primary tumour growth and bone metastasis. Pacritinib had no effect on metastasis in vitro or in vivo. Targeting IL-1 signalling with small molecule inhibitors may provide a new therapeutic strategy for breast cancer bone metastasis.

Item Type:	Article
Additional Information:	This article belongs to the Special Issue Bone Metastasis in Breast Cancer.
Uncontrolled Keywords:	breast cancer; bone metastasis; IL-1beta
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RG Gynecology and obstetrics
Faculty / School / Research Centre / Research Group:	Faculty of Engineering & Science Faculty of Engineering & Science > Biomedical Science Research Group Faculty of Engineering & Science > School of Science (SCI)
Last Modified:	10 Oct 2022 08:03
URI:	http://gala.gre.ac.uk/id/eprint/37559

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