The FAP -activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the AXL pathway.

Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties, a high incidence of pulmonary metastasis and a poor prognosis. Chemotherapy is the mainstay of treatment for osteosarcoma. Currently, there are no molecular targeted drugs approved for osteosarcoma treatment, particularly effective drugs for osteosarcoma with pulmonary metastases. It has been reported that fibroblast activation protein alpha (FAP) is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis, demonstrating that FAP-targeted agents might be a promising therapeutic strategy for osteosarcoma. In the present study, we reported that the FAP-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAP-positive osteosarcoma cells and . Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells. Importantly, it also decreased the migration and invasion capacities and reversed epithelial-mesenchymal transition (EMT) of osteosarcoma cells and suppressed pulmonary metastasis of osteosarcoma xenografts . Mechanistically, Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3/-catenin pathway, leading to inhibition of the growth and metastatic spread of osteosarcoma cells. These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAP-positive osteosarcoma, particularly osteosarcoma with pulmonary metastases.