Research ArticleBONE DEGENERATION

RON kinase: A target for treatment of cancer-induced bone destruction and osteoporosis

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Science Translational Medicine  25 Jan 2017:
Vol. 9, Issue 374, eaai9338
DOI: 10.1126/scitranslmed.aai9338

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A new way to resorb bone

Although bone seems inert, it is in fact in constant flux, being continuously deposited by cells called osteoblasts and broken down by osteoclasts. Andrade et al. show that the bone degeneration seen in diseases, such as cancer and osteoporosis, is caused at least partly by an overexuberant, bone-destroying pathway in which a signaling molecule, MSP, activates its receptor, RON tyrosine kinase, on host cells. Blocking of this signaling by genetic or pharmacologic means prevents bone breakdown in mouse models of metastasis and estrogen- depletion osteoporosis. This welcome approach may work in humans too: A RON kinase inhibitor reduced markers of bone turnover in postmenopausal women.

Abstract

Bone destruction occurs in aging and numerous diseases, including osteoporosis and cancer. Many cancer patients have bone osteolysis that is refractory to state-of-the-art treatments, which block osteoclast activity with bisphosphonates or by inhibiting the receptor activator of nuclear factor κB ligand (RANKL) pathway. We previously showed that macrophage-stimulating protein (MSP) signaling, which is elevated in about 40% of breast cancers, promotes osteolytic bone metastasis by activation of the MSP signaling pathway in tumor cells or in the bone microenvironment. We show that MSP signals through its receptor, RON tyrosine kinase, expressed on host cells, to activate osteoclasts directly by a previously undescribed pathway that is complementary to RANKL signaling and converges on proto-oncogene, non-receptor tyrosine kinase SRC (SRC). Genetic or pharmacologic inhibition of RON kinase blocked cancer-mediated bone destruction and osteoporosis in several mouse models. Furthermore, the RON kinase inhibitor BMS-777607/ASLAN002 altered markers of bone turnover in a first-in-human clinical cancer study, indicating the inhibitor’s potential for normalizing bone loss in patients. These findings uncover a new therapeutic target for pathogenic bone loss and provide a rationale for treatment of bone destruction in various diseases with RON inhibitors.

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