Afatinib ameliorates osteoclast differentiation and function through downregulation of RANK signaling pathways
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초록
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 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 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
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 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 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.
참고문헌 (31)
- Asagiri M, "The molecular understanding of osteoclast differentiation", Bone, 40, pp.251~264 (2007)
- Teitelbaum SL, "Genetic regulation of osteoclast development and function", Nat Rev Genet, 4, pp.638~649 (2003)
- Dougall WC, "RANK is essential for osteoclast and lymph node development", Genes Dev, 13, pp.2412~2424 (1999)
- Kong YY, "OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis", Nature, 397, pp.315~323 (1999)
- Hirsh V, "Zoledronic acid and survival in patients with metastatic bone disease from lung cancer and elevated markers of osteoclast activity", J Thorac Oncol, 3, pp.228~236 (2008)
- D'Antonio C, "Bone and brain metastasis in lung cancer: recent advances in therapeutic strategies", Ther Adv Med Oncol, 6, pp.101~114 (2014)
- Mourskaia AA, "Transforming growth factor-beta1 is the predominant isoform required for breast cancer cell outgrowth in bone", Oncogene, 28, pp.1005~1015 (2009)
- Rossi A, "Bone metastases and non-small cell lung cancer: from bisphosphonates to targeted therapy", Curr Med Chem, 19, pp.5524~5535 (2012)
- Silva SC, "Bone-targeted agents in the treatment of lung cancer", Ther Adv Med Oncol, 7, pp.219~228 (2015)
- Maemondo M, "Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR", N Engl J Med, 362, pp.2380~2388 (2010)
- Zhou C, "Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, openlabel, randomised, phase 3 study", Lancet Oncol, 12, pp.735~742 (2011)
- Kosaka T, "Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib", Clin Cancer Res, 12, pp.5764~5769 (2006)
- Wind S, "Clinical Pharmacokinetics and Pharmacodynamics of Afatinib", Clin Pharmacokinet, 56, pp.235~250 (2017)
- Wang K, "Epidermal growth factor receptor-deficient mice have delayed primary endochondral ossification because of defective osteoclast recruitment", J Biol Chem, 279, pp.53848~53856 (2004)
- Yi T, "Epidermal growth factor receptor regulates osteoclast differentiation and survival through cross-talking with RANK signaling", J Cell Physiol, 217, pp.409~422 (2008)
- Miyauchi Y, "The Blimp1-Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis", J Exp Med, 207, pp.751~762 (2010)
- Zhao B, "Interferon regulatory factor-8 regulates bone metabolism by suppressing osteoclastogenesis", Nat Med, 15, pp.1066~1071 (2009)
- Jurdic P, "Podosome and sealing zone: specificity of the osteoclast model", Eur J Cell Biol, 85, pp.195~202 (2006)
- Teitelbaum SL, "Osteoclasts: what do they do and how do they do it?", Am J Pathol, 170, pp.427~435 (2007)
- Lynch TJ, "Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib", N Engl J Med, 350, pp.2129~2139 (2004)
- Paez JG, "EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy", Science, 304, pp.1497~1500 (2004)
- Li D, "BIBW2992, an irreversible EGFR", HER2 inhibitor highly effective in preclinical lung cancer models, 2008, pp.27, 4702~4711
- Solca F, "Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker", J Pharmacol Exp Ther, 343, pp.342~350 (2012)
- Modjtahedi H, "A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer", Naunyn Schmiedebergs Arch Pharmacol, 387, pp.505~521 (2014)
- Normanno N, "Gefitinib inhibits the ability of human bone marrow stromal cells to induce osteoclast differentiation: implications for the pathogenesis and treatment of bone metastasis", Endocr Relat Cancer, 12, pp.471~482 (2005)
- Furugaki K, "Erlotinib inhibits osteolytic bone invasion of human non-small-cell lung cancer cell line NCI-H292", Clin Exp Metastasis, 28, pp.649~659 (2011)
- Itzstein C, "The regulation of osteoclast function and bone resorption by small GTPases", Small GTPases, 2, pp.117~130 (2011)
- Shostak K, "EGFR and NF-kappaB: partners in cancer", Trends Mol Med, 21, pp.385~393 (2015)
- Bivona TG, "FAS and NF-kappaB signalling modulate dependence of lung cancers on mutant EGFR", Nature, 471, pp.523~526 (2011)
- Ihn HJ, "The 1,2,3-triazole derivative KP-A021 suppresses osteoclast differentiation and function by inhibiting RANKL-mediated MEK-ERK signaling pathway", Exp Biol Med (Maywood), 240, pp.1690~1697 (2015)
- Ihn HJ, "Inhibitory Effects of KP-A159, a Thiazolopyridine Derivative, on Osteoclast Differentiation, Function, and Inflammatory Bone Loss via Suppression of RANKL-Induced MAP Kinase Signaling Pathway", PLoS One, 10, pp.e0142201~ (2015)