The IAP Antagonist SM-164 Eliminates Triple-Negative Breast Cancer Metastasis to Bone and Lung in Mice

Wei Lei,Xin Liu,Alissa Huston,Jinbo Li,Brendan F Boyce,Zhenqiang Yao,Rong Duan

doi:10.1038/s41598-020-64018-z

Abstract

The most challenging issue for breast cancer (BC) patients is metastasis to other organs because current therapies do not prevent or eliminate metastatic BC. Here, we show that SM-164, a small molecule inhibitor, which degrades inhibitor of apoptosis proteins (IAPs), eliminated early-stage metastases and reduced progression of advanced BC metastasis from MDA-MB-231 BC cells in bones and lungs of nude mice. Mechanistically, SM-164-induced BC cell death is TNFα-dependent, with TNFα produced by IL-4-polarized macrophages triggering MDA-MB-231 cell apoptosis in combination with SM-164. SM-164 also inhibited expression of RANKL, which mediates interactions between metastatic BC and host microenvironment cells and induces osteoclast-mediated osteolysis. SM-164 did not kill adriamycin-resistant BC cells, while adriamycin inhibited SM-164-resistant BC cell growth, similar to parental cells. We conclude that SM-164 is a promising therapeutic agent for early stage bone and lung metastasis from triple-negative breast cancer that should be given prior to conventional chemotherapy.

Highlights

The development and progression of breast cancer (BC) metastases depend on interactions between the cancer cells and the host organ microenvironment
In addition to directly inhibiting OC formation by negatively regulating NF-κB signaling in OC precursors through degradation of NF-κB-inducing kinase (NIK)[19], TNF receptor associated factor 3 (TRAF3), an adaptor protein that interacts with cytokine receptors, maintains mesenchymal stem cells (MSCs) differentiation into OBs and inhibits their expression of RANKL, as we reported recently17. cIAP1 and cIAP2 cooperate with TRAF2 to degrade TRAF3 in a variety of cell types, resulting in NF-κB activation[20,21,22]
Adjuvant chemotherapy is widely used after surgical removal of primary breast cancers to kill cancer cells in the circulation and in micro-metastases in organs to prevent recurrence and metastasis, but it benefits only a small proportion (5-10%) of patients and has significant side-effects[2]