A c-Met Inhibitor Suppresses Osteosarcoma Progression via the ERK1/2 Pathway in Human Osteosarcoma Cells

INTRODUCTION: Osteosarcoma is the most common primary malignancy of the bone among adolescents and children. Despite intensive chemotherapy and aggressive surgery, the 5-year survival rate of osteosarcoma still falls under 70%, mainly due to its tendency to metastasize and to develop drug resistance. Therefore, new treatments for osteosarcoma are urgently needed. HGF/c-Met signaling pathway, when dysregulated, is involved in the onset, progression and metastasis of various cancers, making the HGF/c-Met axis a promising therapeutic target. METHODS: In this study, we found Met to be a cancer-promoting gene in osteosarcoma as well, and aimed to investigate the role of a c-met inhibitor (PHA-665752) in osteosarcoma. For this purpose, two human osteosarcoma cell lines (143B and U2OS) were introduced in this study and treated with PHA-665752. CCK8 cell proliferation assay was performed to obtain the IC(50) value of PHA-665752 for 143B and U2OS. After that, colony formation assay, transwell migration and invasion assay and wound-healing assay were performed. Furthermore, a tumor-transplanted mouse model was used for in vivo experiments. RESULTS: Our results showed that PHA-665752 could suppress osteosarcoma progression, promote apoptosis and inhibit proliferation of human osteosarcoma cells. Moreover, we found ERK1/2 pathway to be an important mediator underlying the osteosarcoma-suppressing function of PHA-665752. LY3214996, a highly selective inhibitor of the ERK1/2 pathway, was able to antagonize the effects of PHA-665752 in osteosarcoma. Finally, in vivo experiments indicated that PHA-665752 suppressed tumor growth in a tumor-transplanted mouse model. CONCLUSION: Taken together, Met provided a druggable target for osteosarcoma and PHA-665752 is a promising candidate for anti-osteosarcoma treatments.