Abstract 2121: MET/VEGFR/FMS signaling contributes prostate cancer-induced osteoclast differentiation and bone resorption
Authors: Watanabe Kenta , Hirata Michiko , Tomomi Tsukasa , Matsumoto Chiho , Fujita Hidenori , Yamada Yukari , Matsuo Kenichi , Yonekura Kazuhiko , Miyaura Chisato , Inada Masaki 
Published: August 2018

Abstract
Blockage of both vascular endothelial growth factor (VEGF) receptor and hepatocyte growth factor (HGF) receptor MET signaling pathways has been reported to suppress tumor growth and angiogenesis synergistically, suggesting the possibility that the dual inhibition of VEGFR and MET signals may have potential effects on the prevention of tumor growth. Recently, we developed a novel VEGFR/MET-targeted tyrosine kinase inhibitor, TAS-115, and showed its antitumor properties in xenografts of human gastric carcinoma (Mol Cancer Ther 2013). Although bone metastases frequently occur in prostate cancer patients, the role of VEGF receptor and MET in cancer-induced bone resorption is not known. Patients with advanced prostate cancer show sclerotic bone metastases, which cause chronic pain and pathologic fractures; however, the invasion of prostate cancer cells into bone tissues first induces bone destruction by increased osteoclast-mediated bone resorption. In this study, we used TAS-115, which inhibits both MET and VEGFR, and examined its effects on human prostate cancer cell line (PC3)-induced bone resorption by directly injecting PC3 cells into the proximal medulla of tibiae in nude mouse in vivo, and by the co-culturing of calvarial bone with PC3 cells in vitro. When PC3 cells were injected into proximal tibiae in nude mouse, severe trabecular and cortical bone destruction was detected with subsequent tumor growth. Oral administration of TAS-115 almost completely inhibited both PC3-induced bone loss and PC3 cell proliferation. In an ex vivo bone organ culture, PC3 cells induced osteoclastic bone resorption effectively suppressed by the treatment of TAS-115. In the culture of the bone marrow cells, M-CSF dependent macrophage differentiation and following RANKL-induced osteoclast formation were suppressed by adding TAS-115. FMS-related receptor kinases such as ERK and Akt were also suppressed by the presence of TAS-115. FMS expression was only detected in macrophage and in osteoclast cell lineage. These results indicated that administration of TAS-115 restored bone destruction induced by PC3, mainly by inhibiting the FMS-dependent and RANKL-induced differentiation of preosteoclasts into mature osteoclasts. The additional inhibition of the tyrosine kinase FMS by TAS-115 has profound effects on prostate cancer-driven osteoclastogenesis, and its proliferation extends the capability of this agent to act as a powerful antidote to the devastating effects of metastatic spread to bone.
Citation Format: Kenta Watanabe, Michiko Hirata, Tsukasa Tomomi, Chiho Matsumoto, Hidenori Fujita, Yukari Yamada, Kenichi Matsuo, Kazuhiko Yonekura, Chisato Miyaura, Masaki Inada. MET/VEGFR/FMS signaling contributes prostate cancer-induced osteoclast differentiation and bone resorption [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2121.