The Roadmap of RANKL/RANK Pathway in Cancer

Cells. 2021 Aug 4;10(8):1978. doi: 10.3390/cells10081978.


The receptor activator of the nuclear factor-κB ligand (RANKL)/RANK signaling pathway was identified in the late 1990s and is the key mediator of bone remodeling. Targeting RANKL with the antibody denosumab is part of the standard of care for bone loss diseases, including bone metastases (BM). Over the last decade, evidence has implicated RANKL/RANK pathway in hormone and HER2-driven breast carcinogenesis and in the acquisition of molecular and phenotypic traits associated with breast cancer (BCa) aggressiveness and poor prognosis. This marked a new era in the research of the therapeutic use of RANKL inhibition in BCa. RANKL/RANK pathway is also an important immune mediator, with anti-RANKL therapy recently linked to improved response to immunotherapy in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). This review summarizes and discusses the pre-clinical and clinical evidence of the relevance of the RANKL/RANK pathway in cancer biology and therapeutics, focusing on bone metastatic disease, BCa onset and progression, and immune modulation.

Keywords: RANK ligand (RANKL); bone metastasis; bone-targeted agent; breast cancer; drug repurposing; receptor activator of nuclear factor-κB (RANK); targeted therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Bone Neoplasms / pathology
  • Bone Neoplasms / secondary
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Denosumab / therapeutic use
  • Drug Repositioning
  • Female
  • Humans
  • RANK Ligand / antagonists & inhibitors
  • RANK Ligand / metabolism*
  • Receptor Activator of Nuclear Factor-kappa B / metabolism*
  • Signal Transduction
  • Zoledronic Acid / therapeutic use


  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Denosumab
  • Zoledronic Acid