MSP expressed by metastatic tumor cells activates RON kinase on osteoclasts to promote bone loss.
Major finding: MSP expressed by metastatic tumor cells activates RON kinase on osteoclasts to promote bone loss.
Clinical relevance: A RON inhibitor was well tolerated and reduced markers of bone turnover in postmenopausal women.
Impact: RON inhibition may prevent pathogenic bone destruction in patients with metastatic cancer.
The majority of patients with metastatic breast cancer develop bone metastasis that results in osteolytic bone destruction and bone loss. Although therapies are available to curb bone loss by blocking osteoclast activity, including bisphosphonates and the RANKL antagonist denosumab, cancers that have metastasized to the bone are generally incurable. Macrophage-stimulating protein (MSP) is overexpressed in many breast tumors, promotes bone metastasis, and is the only known ligand of the RON receptor tyrosine kinase, but the role of RON in osteoclasts has not been well defined. Andrade, Fornetti, and colleagues studied the role of MSP–RON signaling in bone loss during bone metastasis and osteoporosis to investigate its potential as a therapeutic target in this context. When injected into mouse tibias, MSP-expressing tumor cells induced extensive osteolysis of wild-type bones but not of RON−/− bones, indicating that tumor cell MSP requires host RON activity to induce bone destruction. The MSP-mediated osteolysis resulted from increased osteoclast activity, which could be reduced by small-molecule inhibition of RON. In vivo, RON inhibitors halted tumor-driven osteolysis and bone loss. Although RANKL and TGFβ contribute to osteoclast activation in the tumor microenvironment, MSP-driven osteolysis was independent of these pathways. Instead, metastatic tumor MSP activated RON on osteoclasts, resulting in downstream phosphorylation and activation of SRC to induce osteolysis. These findings are also relevant to osteoporotic osteolysis, and RON inhibitors similarly protected against bone loss in mice with ovariectomy-induced osteoporosis. These results supported further clinical investigation of RON inhibitors to reduce bone loss. A phase I clinical trial evaluating a RON inhibitor in patients with cancer indicated that RON inhibition was well tolerated and reduced markers of bone turnover in postmenopausal women. Collectively, these findings elucidate a mechanism by which MSP promotes osteoclast activity, and suggest that RON may be a therapeutic target to prevent metastasis-associated bone destruction.
Andrade K, Fornetti J, Zhao L, Miller SC, Randall RL, Anderson N, et al. RON kinase: A target for treatment of cancer-induced bone destruction and osteoporosis. Sci Transl Med 2017;9.pii: eaai9338.
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