The Role of the RANKL/RANK Axis in the Prevention and Treatment of Breast Cancer with Immune Checkpoint Inhibitors and Anti-RANKL.

Aristofania Simatou,Panagiotis Sarantis,Athanasios G Papavassiliou,Evangelos Koustas,Michalis V Karamouzis

doi:10.3390/ijms21207570

Aristofania Simatou, Panagiotis Sarantis + Show 3 more

Open Access

https://doi.org/10.3390/ijms21207570

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Abstract

The receptor activator of nuclear factor-κB (RANK) and the RANK ligand (RANKL) were reported in the regulation of osteoclast differentiation/activation and bone homeostasis. Additionally, the RANKL/RANK axis is a significant mediator of progesterone-driven mammary epithelial cell proliferation, potentially contributing to breast cancer initiation and progression. Moreover, several studies supported the synergistic effect of RANK and epidermal growth factor receptor (EGFR) and described RANK’s involvement in epidermal growth factor receptor 2 (ERBB2)-positive carcinogenesis. Consequently, anti-RANKL treatment has been proposed as a new approach to preventing and treating breast cancer and metastases. Recently, RANKL/RANK signaling pathway inhibition has been shown to modulate the immune environment and enhance the efficacy of anti-CTLA-4 and anti-PD-1 monoclonal antibodies against solid tumors. Clinical and experimental trials have emerged evaluating RANKL inhibition as an enhancer of the immune response, rendering resistant tumors responsive to immune therapies. Trials evaluating the combinatorial effect of immune checkpoint inhibitors and anti-RANKL treatment in double-positive (RANK+/ERBB2+) patients are encouraging.

Highlights

The receptor activator of nuclear factor-κB (RANK) and the RANK ligand (RANKL) were reported in the regulation of osteoclast differentiation/activation and bone homeostasis
The RANKL/RANK axis is closely associated with tumorigenesis initiation and progression in breast cancer
The impaired regulation of the RANKL/RANK axis seems to possess a critical role in promoting bone metastases through the secretion of cytokines by breast cancer (BC), which cause increased RANKL production by stromal cells in the bone microenvironment

Summary

Clinical Trials with Denosumab

Clinical studies have tried to evaluate the beneficial effect of denosumab, alone or in combination, on patients with early-stage or metastatic breast cancer in order to identify the role of denosumab alone (ClinicalTrials.gov Identifiers: NCT03324932, NCT03691311, NCT02613416, NCT01419717). In the study with ClinicalTrials.gov Identifier NCT01077154, denosumab did not improve disease-related outcomes for women with high-risk early breast cancer [63]. The findings of a multivariate analysis with ClinicalTrials.gov NCT01545648 revealed bone marrow (BM) and disseminated tumor cells’ (DTCs) positivity as an independent risk factor for disease-free survival (DFS), in luminal A/B BC patients. This might be a novel criterion for the identification of patients most likely to benefit from additional adjuvant therapy, possibly including bisphosphonates (denosumab) [64]. Recruiting Terminated, has results [63] Active, not recruiting Terminated, has results [64]

Metastatic disease

Mechanisms Involved in the Treatment with RANKL and ICIs

Findings

10. Conclusions