Inhibition of RANKL increases the anti-tumor effect of the EGFR inhibitor panitumumab in a murine model of bone metastasis

Bone. 2010 Jun;46(6):1613-9. doi: 10.1016/j.bone.2010.03.001. Epub 2010 Mar 6.


Bone metastases cause severe skeletal complications and are associated with osteoclast-mediated bone destruction. RANKL is essential for osteoclast formation, function, and survival, and is the primary effector of tumor-induced osteoclastogenesis and osteolysis. RANKL inhibition by its soluble decoy receptor osteoprotegerin (OPG) prevents tumor-induced osteolysis and decreases skeletal tumor burden. Because osteoclast-mediated bone resorption releases growth factors from the bone matrix, the host bone microenvironment induces a vicious cycle of bone destruction and tumor proliferation and survival. A prediction of this vicious cycle hypothesis is that targeting the host bone microenvironment by osteoclast inhibition would reduce tumor growth and survival and may enhance the anti-tumor effects of targeted therapies. The epidermal growth factor receptor (EGFR) pathway regulates critical processes such as cell growth and survival, and anti-EGFR therapies can cause tumor cell arrest and apoptosis. We evaluated whether reduction of osteolysis by RANKL inhibition could enhance the anti-tumor effects of an anti-EGFR antibody (panitumumab) in a novel murine model of human A431 epidermoid carcinoma bone metastasis. Skeletal tumor progression was assessed longitudinally by bioluminescence imaging. RANKL inhibition by OPG-Fc treatment resulted in a reduction in tumor progression in bony sites. OPG-Fc treatment also caused a dose-dependent reduction in tumor-induced osteolysis, supporting the essential role of RANKL in this process. In combination, RANKL inhibition increased the anti-tumor efficacy of an anti-EGFR antibody, and completely blocked tumor-induced bone breakdown, demonstrating that addition of the indirect anti-tumor effect of RANKL inhibition increases the anti-tumor efficacy of panitumumab, a targeted anti-EGFR antibody.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Bone Neoplasms / drug therapy
  • Bone Neoplasms / secondary
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / secondary
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • ErbB Receptors / antagonists & inhibitors*
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis
  • Osteoprotegerin / pharmacology
  • Panitumumab
  • RANK Ligand / antagonists & inhibitors*
  • Random Allocation


  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Osteoprotegerin
  • RANK Ligand
  • Panitumumab
  • EGFR protein, mouse
  • ErbB Receptors