Ihn Hye Jung, Kim Ju Ang, Bae Yong Chul, Shin Hong-In, Baek Moon-Chang, Park Eui Kyun
Departments of Oral Pathology and Regenerative Medicine, Kyungpook National University, Daegu 41940, Korea.
Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 41940, Korea.
BMB Rep. 2017 Mar;50(3):150-155. 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].
非小细胞肺癌（NSCLC）是第三大最常转移至骨骼的癌症，可导致因破骨细胞过度活化引起的溶骨性病变。表皮生长因子受体酪氨酸激酶（EGF-TK）激活突变常与NSCLC相关，阿法替尼是一种不可逆靶向EGF-TK的一线治疗药物。然而，阿法替尼对破骨细胞分化和活化的影响及其潜在机制仍不清楚。在本研究中，阿法替尼显著抑制骨髓巨噬细胞（BMMs）中核因子κB受体激活剂（RANK）配体（RANKL）诱导的破骨细胞形成。同样，阿法替尼抑制破骨细胞标志物基因的表达，而上调负性调节基因的表达。阿法替尼还消除了破骨细胞的骨吸收活性。此外，阿法替尼显著抑制RANKL介导的Akt/蛋白激酶B和c-Jun氨基末端激酶磷酸化。这些结果表明，阿法替尼通过下调RANK信号通路显著抑制破骨细胞生成，因此可能减少骨转移后的骨溶解。[《BMB报告》2017；50(3): 150 - 155]
