The RANK-RANKL axis: an opportunity for drug repurposing in cancer?

Clin Transl Oncol. 2019 Aug;21(8):977-991. doi: 10.1007/s12094-018-02023-5. Epub 2019 Jan 17.


Drug repurposing offers advantages over traditional drug development in terms of cost, speed and improved patient outcomes. The receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) inhibitor denosumab is approved for the prevention of skeletal-related events in patients with advanced malignancies involving bone, including solid tumours and multiple myeloma. Following improved understanding of the role of RANK/RANKL in cancer biology, denosumab has already been repurposed as a treatment for giant cell tumour of bone. Here, we review the role of RANK/RANKL in tumourigenesis, including effects on tumour initiation, progression and metastasis and consider the impact of RANK/RANKL on tumour immunology and immune evasion. Finally, we look briefly at ongoing trials and future opportunities for therapeutic synergy when combining denosumab with anti-cancer agents such as immune checkpoint inhibitors.

Keywords: Checkpoint; Denosumab; Immunotherapy; Osteoprotegerin; RANK; RANKL.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Drug Repositioning*
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism*
  • Prognosis
  • RANK Ligand / metabolism*
  • Receptor Activator of Nuclear Factor-kappa B / metabolism*


  • Antineoplastic Agents
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • TNFRSF11A protein, human
  • TNFSF11 protein, human