The Roadmap of RANKL/RANK Pathway in Cancer

Abstract

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.

Figure 1

Pre-clinical and clinical landmarks of RANKL/RANK pathway research in Oncology. ADT, androgen deprivation therapy; AI, aromatase inhibitors; BCa, breast cancer; BM, bone metastases; ccRCC, clear cell renal cell carcinoma; ICI, immune checkpoint inhibitor; MM, multiple myeloma; PCa, prostate cancer; Pg, progesterone; SREs, skeletal-related effects; ZA, Zoledronate.

Figure 2

RANKL inhibition in bone metastases (BM). Bone-targeted agents (BTAs) are used to control BM by impairing bone resorption, indirectly affecting the tumor burden. While bisphosphonates only affect mature osteoclasts, inducing apoptosis, the anti-RANKL antibody denosumab prevents osteoclast differentiation, activity, and survival. Denosumab may also be antiangiogenic over RANK-positive endothelial cells. RANK is expressed in dendritic cells (DC) and macrophages, like tumor-associated macrophages (TAMs), and T-cell derived RANKL inhibition decreases TAMs and increases cytotoxic T cells. Potential direct effects of BTAs in tumor cells include inhibition of proliferation and migration and induction of apoptosis.

Figure 3

The role of RANKL/RANK signaling in the breast spans from physiologic development to breast cancer (BCa). RANKL expression in mammary epithelial cells is regulated by progesterone (Pg)-activated receptors and activates RANK in RANK-expressing luminal and basal cells, promoting proliferation, differentiation, migration, and survival. Expansion of mammary stem cells is associated with carcinogenesis. In BCa cells, RANKL-RANK signaling pathway is associated with aggressiveness features independently of subtype, including epithelial-to-mesenchymal transition (EMT), stemness, migration, metastases and therapy resistance.