The MET/Vascular Endothelial Growth Factor Receptor (VEGFR)-targeted Tyrosine Kinase Inhibitor Also Attenuates FMS-dependent Osteoclast Differentiation and Bone Destruction Induced by Prostate Cancer

Abstract

The tyrosine kinase inhibitor TAS-115 that blocks VEGF receptor and hepatocyte growth factor receptor MET signaling exhibits antitumor properties in xenografts of human gastric carcinoma. In this study, we have evaluated the efficacy of TAS-115 in preventing prostate cancer metastasis to the bone and bone destruction using the PC3 cell line. When PC3 cells were injected into proximal tibiae in nude mouse, severe trabecular and cortical bone destruction and subsequent tumor growths were detected. Oral administration of TAS-115 almost completely inhibited both PC3-induced bone loss and PC3 cell proliferation by suppressing osteoclastic bone resorption. In an ex vivo bone organ culture, PC3 cells induced osteoclastic bone resorption when co-cultured with calvarial bone, but TAS-115 effectively suppressed the PC3-induced bone destruction. We found that macrophage colony-stimulating factor-dependent macrophage differentiation and subsequent receptor activator of NF-B ligand-induced osteoclast formation were largely suppressed by adding TAS-115. The phosphorylation of the macrophage colony-stimulating factor receptor FMS and osteoclast related kinases such as ERK and Akt were also suppressed by the presence of TAS-115. Gene expression profiling showed that FMS expression was only seen in macrophage and in the osteoclast cell lineage. Our study indicates that tyrosine kinase signaling in host pre-osteoclasts/osteoclasts is critical for bone destruction induced by tumor cells and that targeting of MET/VEGF receptor/FMS activity makes it a promising therapeutic candidate for the treatment of prostate cancer patients with bone metastasis.VEGF signaling through the tyrosine kinase receptor VEGF receptor (VEGFR) 3 is a pivotal factor for tumor angiogenesis that regulates tumor progression. However, VEGFR-targeted inhibitor monotherapies showed limited effects on various carcinomas, and even combination therapies with chemotherapeutic agents are unsatisfactory (1, 2). The tyrosine kinase MET is a receptor for hepatocyte growth factor (HGF), and HGF-MET signaling is also involved in tumor progression, metastasis, angiogenesis, and resistance to chemotherapy in various cancers, indicating that MET kinase inhibitors could have major therapeutic potential. Inhibition of both VEGFR and MET signaling pathways has been reported to suppress tumor growth and angiogenesis synergistically (3), suggesting the possibility that the dual inhibition of VEGFR and MET signals may have potential effects on the prevention of tumor growth. Recently, Fujita et al. (4) developed a novel VEGFR/MET-targeted tyrosine kinase inhibitor, TAS-115, and showed its antitumor properties in MET-amplified human cancer-bearing mice. In this study, we have investigated the effect of TAS-115 on prostate cancer cell metastasis to bone and a process associated with osteoclast activation.Bone remodeling is regulated by osteoclastic bone resorption and new bone formation. Osteoclasts, which are the primary bone-resorbing cells, are differentiated from macrophages b...

Blocking MET receptor signaling in multiple myeloma cells in vitro and in vivo

“…5,7,[14][15][16] This axis is also important in oncogenesis and plays a significant role in the migration, proliferation and adhesion of various neoplastic cells. Overexpression or excessive activation of HGF/MET has been demonstrated in mesenchymal and epithelial tumors such as breast cancer, ovarian cancer, gastrointestinal tract cancer, lung cancer, prostate cancer, glioblastoma, sarcomas, and MM.…”

Bone-Targeted Therapies in Cancer-Induced Bone Disease

“…Additional proof for the direct effect of cabozantinib in prostate cancer tumour cells, endothelial cells and osteoblasts was provided by patient derived xenografts and clinical trials [175]. A study with TAS-115, another MET/VEGFR inhibitor that also inhibits FMS, demonstrated an osteolysis prevention effect (PC-3 model) due to prostate cancer cell and osteoclast targeting (the latter via inhibition of FMS-dependent RANKL-induced pre-osteoclast to osteoclast differentiation) [176]. Similar results emerged from a model of bone metastatic lung carcinoma [177].…”

Bone scan index: A new biomarker of bone metastasis in patients with prostate cancer

“…The role of BSI in the management of patients with prostate cancer will be analyzed after a follow‐up period of 3 years. A new phase 2 clinical study is under investigation in patients with CRPC (JapicCTI‐163448) in Japan to assess the efficacy and safety of TAS‐115 (vascular endothelial growth factor receptor‐targeted tyrosine kinase inhibitor; Taiho Pharmaceutical, Tokyo, Japan) . The primary outcome of that study uses BSI calculated with BONENAVI software.…”

“…A new phase 2 clinical study is under investigation in patients with CRPC (JapicCTI-163448) in Japan to assess the efficacy and safety of TAS-115 (vascular endothelial growth factor receptor-targeted tyrosine kinase inhibitor; Taiho Pharmaceutical, Tokyo, Japan). 22 The primary outcome of that study uses BSI calculated with BONE-NAVI software. BSI could be a good surrogate marker for evaluating the effects of potentially useful new drugs for bone metastasis.…”