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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Afatinib ameliorates osteoclast differentiation and function through downregulation of RANK signaling pathways

  • Ihn, Hye Jung (Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Kyungpook National University) ;
  • Kim, Ju Ang (Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Kyungpook National University) ;
  • Bae, Yong Chul (Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University) ;
  • Shin, Hong-In (Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Kyungpook National University) ;
  • Baek, Moon-Chang (Department of Molecular Medicine, CMRI, School of Medicine, Kyungpook National University) ;
  • Park, Eui Kyun (Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Kyungpook National University)
  • Received : 2016.12.21
  • Accepted : 2017.02.25
  • Published : 2017.03.31
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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) 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 ${\kappa}B$ (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.

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References

  1. Asagiri M and Takayanagi H (2007) The molecular understanding of osteoclast differentiation. Bone 40, 251-264 https://doi.org/10.1016/j.bone.2006.09.023
  2. Teitelbaum SL and Ross FP (2003) Genetic regulation of osteoclast development and function. Nat Rev Genet 4, 638-649 https://doi.org/10.1038/nrg1122
  3. Dougall WC, Glaccum M, Charrier K et al (1999) RANK is essential for osteoclast and lymph node development. Genes Dev 13, 2412-2424 https://doi.org/10.1101/gad.13.18.2412
  4. Kong YY, Yoshida H, Sarosi I et al (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315-323 https://doi.org/10.1038/16852
  5. Hirsh V, Major PP, Lipton A et al (2008) Zoledronic acid and survival in patients with metastatic bone disease from lung cancer and elevated markers of osteoclast activity. J Thorac Oncol 3, 228-236 https://doi.org/10.1097/JTO.0b013e3181651c0e
  6. D'Antonio C, Passaro A, Gori B et al (2014) Bone and brain metastasis in lung cancer: recent advances in therapeutic strategies. Ther Adv Med Oncol 6, 101-114 https://doi.org/10.1177/1758834014521110
  7. Mourskaia AA, Dong Z, Ng S et al (2009) Transforming growth factor-beta1 is the predominant isoform required for breast cancer cell outgrowth in bone. Oncogene 28, 1005-1015 https://doi.org/10.1038/onc.2008.454
  8. Rossi A, Gridelli C, Ricciardi S and de Marinis F (2012) Bone metastases and non-small cell lung cancer: from bisphosphonates to targeted therapy. Curr Med Chem 19, 5524-5535 https://doi.org/10.2174/092986712803833209
  9. Silva SC, Wilson C and Woll PJ (2015) Bone-targeted agents in the treatment of lung cancer. Ther Adv Med Oncol 7, 219-228 https://doi.org/10.1177/1758834015582178
  10. Maemondo M, Inoue A, Kobayashi K et al (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362, 2380-2388 https://doi.org/10.1056/NEJMoa0909530
  11. Zhou C, Wu YL, Chen G et al (2011) 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, 735-742 https://doi.org/10.1016/S1470-2045(11)70184-X
  12. Kosaka T, Yatabe Y, Endoh H et al (2006) 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, 5764-5769 https://doi.org/10.1158/1078-0432.CCR-06-0714
  13. Wind S, Schnell D, Ebner T, Freiwald M and Stopfer P (2017) Clinical Pharmacokinetics and Pharmacodynamics of Afatinib. Clin Pharmacokinet 56, 235-250 https://doi.org/10.1007/s40262-016-0440-1
  14. Wang K, Yamamoto H, Chin JR, Werb Z and Vu TH (2004) Epidermal growth factor receptor-deficient mice have delayed primary endochondral ossification because of defective osteoclast recruitment. J Biol Chem 279, 53848-53856 https://doi.org/10.1074/jbc.M403114200
  15. Yi T, Lee HL, Cha JH et al (2008) Epidermal growth factor receptor regulates osteoclast differentiation and survival through cross-talking with RANK signaling. J Cell Physiol 217, 409-422 https://doi.org/10.1002/jcp.21511
  16. Miyauchi Y, Ninomiya K, Miyamoto H et al (2010) The Blimp1-Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis. J Exp Med 207, 751-762 https://doi.org/10.1084/jem.20091957
  17. Zhao B, Takami M, Yamada A et al (2009) Interferon regulatory factor-8 regulates bone metabolism by suppressing osteoclastogenesis. Nat Med 15, 1066-1071 https://doi.org/10.1038/nm.2007
  18. Jurdic P, Saltel F, Chabadel A and Destaing O (2006) Podosome and sealing zone: specificity of the osteoclast model. Eur J Cell Biol 85, 195-202 https://doi.org/10.1016/j.ejcb.2005.09.008
  19. Teitelbaum SL (2007) Osteoclasts: what do they do and how do they do it? Am J Pathol 170, 427-435 https://doi.org/10.2353/ajpath.2007.060834
  20. Lynch TJ, Bell DW, Sordella R et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350, 2129-2139 https://doi.org/10.1056/NEJMoa040938
  21. Paez JG, Janne PA, Lee JC et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497-1500 https://doi.org/10.1126/science.1099314
  22. Li D, Ambrogio L, Shimamura T et al (2008) BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27, 4702-4711 https://doi.org/10.1038/onc.2008.109
  23. Solca F, Dahl G, Zoephel A et al (2012) Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther 343, 342-350 https://doi.org/10.1124/jpet.112.197756
  24. Modjtahedi H, Cho BC, Michel MC and Solca F (2014) A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer. Naunyn Schmiedebergs Arch Pharmacol 387, 505-521 https://doi.org/10.1007/s00210-014-0967-3
  25. Normanno N, De Luca A, Aldinucci D et al (2005) 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, 471-482 https://doi.org/10.1677/erc.1.00956
  26. Furugaki K, Moriya Y, Iwai T et al (2011) Erlotinib inhibits osteolytic bone invasion of human non-small-cell lung cancer cell line NCI-H292. Clin Exp Metastasis 28, 649-659 https://doi.org/10.1007/s10585-011-9398-4
  27. Itzstein C, Coxon FP and Rogers MJ (2011) The regulation of osteoclast function and bone resorption by small GTPases. Small GTPases 2, 117-130 https://doi.org/10.4161/sgtp.2.3.16453
  28. Shostak K and Chariot A (2015) EGFR and NF-kappaB: partners in cancer. Trends Mol Med 21, 385-393 https://doi.org/10.1016/j.molmed.2015.04.001
  29. Bivona TG, Hieronymus H, Parker J et al (2011) FAS and NF-kappaB signalling modulate dependence of lung cancers on mutant EGFR. Nature 471, 523-526 https://doi.org/10.1038/nature09870
  30. Ihn HJ, Lee D, Lee T et al (2015) 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, 1690-1697 https://doi.org/10.1177/1535370215576310
  31. Ihn HJ, Lee D, Lee T et al (2015) 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, e0142201 https://doi.org/10.1371/journal.pone.0142201

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