Antagonism of Inhibitor of Apoptosis Proteins Increases Bone Metastasis via Unexpected Osteoclast Activation

Abstract

Although IAP antagonists are a class of anticancer agents with proven efficacy in multiple cancers, we show that these agents can paradoxically increase tumor growth and metastasis in the bone by stabilizing NIK and activating the alternative NF-κB pathway in osteoclasts. Future clinical trials of IAP antagonist-based therapy may require detailed examination of this potential for enhanced bone metastasis and osteoporosis, as well as possible combination with antiresorptive agents.