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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) 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 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 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.