title: Afatinib ameliorates osteoclast differentiation and function through downregulation of RANK signaling pathways.
abstract: 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].
authors.affiliation: Departments of Oral Pathology and Regenerative Medicine, Kyungpook National University, Daegu 41940, Korea.
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Ihn
authors.affiliation: Departments of Oral Pathology and Regenerative Medicine, Kyungpook National University, Daegu 41940, Korea.
authors.forename: Ju Ang
authors.initials: JA
authors.lastname: Kim
authors.affiliation: Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 41940, Korea.
authors.forename: Yong Chul
authors.initials: YC
authors.lastname: Bae
authors.affiliation: Departments of Oral Pathology and Regenerative Medicine, Kyungpook National University, Daegu 41940, Korea.
authors.forename: Hong-In
authors.initials: HI
authors.lastname: Shin
authors.affiliation: Department of Molecular Medicine, CMRI, School of Medicine, Kyungpook National University, Daegu 41944, Korea.
authors.forename: Moon-Chang
authors.initials: MC
authors.lastname: Baek
authors.affiliation: Departments of Oral Pathology and Regenerative Medicine, Kyungpook National University, Daegu 41940, Korea.
authors.forename: Eui Kyun
authors.initials: EK
authors.lastname: Park
mesh_terms: D000077716:Afatinib; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D001862:Bone Resorption / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology*; D010766:Phosphorylation; D011799:Quinazolines / Q000378:metabolism* / Q000627:therapeutic use; D053245:RANK Ligand / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016328:NF-kappa B; D011799:Quinazolines; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D000077716:Afatinib; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases