Inhibition of discoidin domain receptor 1 (DDR1) as a new therapeutic strategy for osteosarcoma

Abstract

Abstract Osteosarcoma is the most common type of bone cancer. Some patients eventually develop recurrent or metastatic diseases and treatment options are extremely limited. Discoidin domain receptor 1 (DDR1) is a unique collagen-activated tyrosine kinase that participates in various human diseases, including cancer. DDR1 promotes adhesion, proliferation, differentiation, migration, and metastasis of cancer cells. However, the expression and function of DDR1 remain unknown in osteosarcoma. The purpose of this study is to assess the expression, clinical prognostic relationship and functional roles of DDR1 in osteosarcoma. The correlation between DDR1 expression in tumor tissues and clinicopathological features, and prognosis was assessed via immunohistochemical staining of a unique tissue microarray (TMA) constructed from osteosarcoma specimens. DDR1-specific siRNA and a highly selective DDR1 inhibitor, 7rh, were applied to determine the impact of DDR1 expression on osteosarcoma cell growth and proliferation. Furthermore, the effect of DDR1 inhibition on clonogenicity was evaluated using a clonogenic assay, and a 3D cell culture model was used to mimic DDR1 effects in an in vivo environment. The results demonstrate that higher DDR1 expression significantly correlates with recurrence, metastasis, and shorter overall survival in osteosarcoma patients. The expression of DDR1 is also inversely correlated to the response to neoadjuvant chemotherapy. Therapeutically, DDR1 knockdown with siRNA or selective inhibition with 7rh decreases the proliferation and growth of osteosarcoma cells. In conclusion, our study supports DDR1 expression as an independent predictor of poor prognosis and a promising therapeutic target for osteosarcoma.