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Osteosarcoma (OS) is the most common nonhematologic bone malignancy in children and adolescents. Despite the advances of adjuvant chemotherapy and significant improvement of survival, the prognosis remains generally poor. As such, the search for more effective anti-OS agents is urgent. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is thought to be one of the most important oncogenic pathways in human cancer. An increasing body of evidence has shown that this pathway is frequently hyperactivated in OS and contributes to disease initiation and development, including tumorigenesis, proliferation, invasion, cell cycle progression, inhibition of apoptosis, angiogenesis, metastasis and chemoresistance. Inhibition of this pathway through small molecule compounds represents an attractive potential therapeutic approach for OS. The aim of this review is to summarize the roles of the PI3K/Akt pathway in the development and progression of OS, and to highlight the therapeutic potential of targeting this signaling pathway. Knowledge obtained from the application of these compounds will help in further understanding the pathogenesis of OS and designing subsequent treatment strategies.
•Activation of the PI3K/Akt signaling regulates various cellular functions.•The PI3K/Akt signaling may play a key role in the progression of osteosarcoma.•Targeting the PI3K/Akt signaling has therapeutic potential for osteosarcoma.