Current progress and open challenges for applying tyrosine kinase inhibitors in osteosarcoma.

Osteosarcoma (OS) is a mesenchymal-origin tumor that constitutes the most common primary malignant bone tumor. The survival rate of the patients has significantly improved since the introduction of neoadjuvant chemotherapy and extensive resection, but it has stagnated in recent 40 years. Tyrosine kinase inhibitors (TKIs) have played a key part in the treatment of malignant tumors. In advanced OS, TKIs including anlotinib, apatinib, sorafenib, etc. have significantly improved the progression-free survival of patients, while the overall survival remains unchanged. The main reason is the rapid and inevitable progress of acquired drug resistance of OS. However, as the application of TKIs in OS and other tumors is still in the exploratory phase, its drug resistance mechanism and corresponding solutions are rarely reported. Hence, in this review, we summarize knowledge of the applications of TKIs, the mechanism of TKIs resistance, and the attempts to overcome TKIs resistance in OS, which are the three potentially novel insights of TKIs in OS. Because most evidence is derived from studies using animal and cell models, we also reviewed clinical trials and related bioinformatics data available in public databases, which partially improved our understanding of TKIs applications.