MST1R Inhibitor Prevents Bone Osteolysis

RESEARCH HIGHLIGHTS

Nature Reviews Drug Discovery | Published online 1 Mar 2017; doi:10.1038/nrd.2017.30

BONE DISEASES MST1R inhibitor prevents bone osteolysis

Bone osteolysis occurs in patients To further investigate the role of on SRC. So, MST1R and RANKL with metastatic cancer or osteoporosis MSP, Andrade et al. studied MST1R- are likely to activate SRC through and can lead to an increased risk of genetic deficient mice. They found that different mechanisms. fracture as well as pain. Now, Andrade deficiency of these mice are resistant to osteolysis, In ovarectomized mice, a model et al. have found that inhibiting including following tumour cell of osteoporosis, genetic deficiency of macrophage-stimulating protein MST1R or transplantation in immunodeficient MST1R or pharmacological inhibi- receptor (MST1R; also known as pharmacological mice, which suggests that MST1 has tion with BMS-777607 every other RON) blocks bone destruction in mice inhibition ... a role in the bone rather than the day for 28 days protected mice from with metastatic breast tumours or protected mice tumour. Pharmacological inhibition bone loss. that have undergone ovariectomy. An of MST1R by oral gavage with either In a phase I clinical trial of MST1R inhibitor also decreased bone from bone loss OSI-296 or BMS-777607 (both BMS-777607 in patients with cancer, turnover in a phase I clinical trial that of which also inhibit the related 13 out of 21 individuals treated with included postmenopausal women. receptor, MET) had similar effects. BMS-777607 showed decreased MST1R is a receptor tyrosine OSI-296, but not BMS-777607, also levels of cleaved bone-derived col- kinase that is expressed in osteo- reduced tumour growth in the bone. lagen in plasma, which is a marker clasts and other tissues (including Next, the authors set out to of bone turnover. Approximately macrophages) and serves as the explore the downstream effects of two-thirds of these patients had receptor for macrophage-stimulating MST1R activation. Denosumab is large enough drops to meet Mayo protein (MSP; also known as hepato a receptor activator of nuclear factor Clinic guidelines for a response to cyte growth factor-like protein). κB ligand (RANKL) antagonist that bone antiresorptive therapies. The Previously, this group had shown that is approved by the US Food and best results were seen in women, expression of MSP in mouse mam- Drug Administration (FDA) to treat most of whom were over 50 years old mary tumours led to spontaneous bone metastasis and osteoporosis. and are therefore expected to have osteolytic bone metastasis. Stimulation of either RANKL or increased bone turnover as a result MST1R results in SRC activation, of menopause. so the authors investigated whether These data suggest that MST1R these pathways overlap. In their inhibitors could be used to prevent model, an anti-RANKL antibody bone loss in patients with advanced fragment (muRANK-Fc) had effects cancers or osteoporosis, possibly that were distinct from those of in combination with existing treat- the MST1R inhibitors: although ments, such as RANKL inhibitors. muRANK-Fc decreased osteolysis The authors highlight that MSP is in mouse tumour models, this treat- also selectively overexpressed in ment was not effective if the tumour multiple myeloma and lung cancer, cells overexpressed high levels of so MST1R inhibitors could be MSP. In osteoclasts ex vivo, both MSP particularly useful in those tumour and RANK increased osteoclast sur- types as well. vival and activation, but only RANK Megan Cully

promoted osteoclast differentiation. ORIGINAL ARTICLE Andrade, K. et al. RON Furthermore, MSP and RANK stim- kinase: a target for treatment of cancer-induced ulation resulted in the phosphoryl bone destruction and osteoporosis. Sci. Transl Med. 9, eaai9338 (2017) ation of different tyrosine residues Panther Media GmbH/Alamy Stock Photo