Novel Methods of Targeting IL-1 Signalling for the Treatment of Breast Cancer Bone Metastasis

SIMPLE SUMMARY: The pro-inflammatory cytokine, IL1β, plays a pivotal role in breast cancer bone metastasis. Inhibiting IL-1 signalling with the IL1β specific antibody, Canakinumab, or the IL1R1 antagonist Anakinra almost eliminates bone metastases but has adverse effects on tumours growing outside of the bone and immune regulation. This current study demonstrated that pharmacological inhibition of other members of the IL-1 signalling pathway Caspase-1, IL1β and IL1R reduced migration and invasion of E0771 and Py8119 cells in vitro and also reduced spontaneous metastasis and metastatic outgrowth of breast cancer in the bone, in vivo. Interestingly, targeting IRAK1 had no anti-tumour effects. Importantly, inhibiting Caspase-1 reduces bone metastasis without adversely affecting tumours outside of bone or immune cell regulation, suggesting that targeting immediately upstream of IL1β may be a good therapeutic strategy for treating patients with breast-cancer-induced bone disease. 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.