Afatinib ameliorates osteoclast differentiation and function through downregulation of RANK signaling pathways

• Published in: BMB reports Vol. 50; no. 3; pp. 150 - 155
• Main Authors: Ihn, Hye Jung, Kim, Ju Ang, Bae, Yong Chul, Shin, Hong-In, Baek, Moon-Chang, Park, Eui Kyun
• Format: Journal Article
• Language: English
• Published: Korea (South) Korean Society for Biochemistry and Molecular Biology 01.03.2017; 생화학분자생물학회
• Subjects: Afatinib; Animals; Bone Marrow Cells - cytology; Bone Resorption - pathology; Cell Differentiation - drug effects; Down-Regulation - drug effects; ErbB Receptors - metabolism; JNK Mitogen-Activated Protein Kinases - metabolism; Macrophages - drug effects; Mice; NF-kappa B - metabolism; Osteoclasts - cytology; Phosphorylation; Quinazolines - metabolism; Quinazolines - therapeutic use; RANK Ligand - drug effects; RANK Ligand - genetics; RANK Ligand - metabolism; Receptor Activator of Nuclear Factor-kappa B - metabolism; Signal Transduction - drug effects; 화학
• ISSN: 1976-6696; 1976-670X
• DOI: 10.5483/BMBRep.2017.50.3.223

Non-small-cell lung cancer (NSCLC) is the third most common cancer that spreads to the bone, resulting in osteolytic lesions caused by hyperactivation of osteoclasts. Activating mutations in epidermal growth factor receptor-tyrosine kinase (EGF-TK) are frequently associated with NSCLC, and afatinib is a first-line therapeutic drug, irreversibly targeting EGF-TK. However, the effects of afatinib on osteoclast differentiation and activation as well as the underlying mechanism remain unclear. In this study, afatinib significantly suppressed receptor activator of nuclear factor κB (RANK) ligand (RANKL)-induced osteoclast formation in bone marrow macrophages (BMMs). Consistently, afatinib inhibited the expression of osteoclast marker genes, whereas, it upregulated the expression of negative modulator genes. The bone resorbing activity of osteoclasts was also abrogated by afatinib. In addition, afatinib significantly inhibited RANKL-mediated Akt/protein kinase B and c-Jun N-terminal kinase phosphorylation. These results suggest that afatinib substantially suppresses osteoclastogenesis by downregulating RANK signaling pathways, and thus may reduce osteolysis after bone metastasis. [BMB Reports 2017; 50(3): 150-155].