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Afatinib ameliorates osteoclast differentiation and function through downregulation of RANK signaling pathways
Hye Jung Ihn1, Ju Ang Kim1, Yong Chul Bae2, Hong-In Shin1, Moon-Chang Baek3, Eui Kyun Park1,*
1Oral Pathology and Regenerative Medicine and 2Anatomy and Neurobiology, Kyungpook National University,
3Molecular Medicine, Kyungpook National University
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) is 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. Afatinib dramatically suppressed receptor activator of nuclear factor リB (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 dramatically 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.
Abstract, Accepted Manuscript(in press) [Submitted on December 21, 2016, Accepted on February 25, 2017]
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