Receptor Tyrosine Kinases in Osteosarcoma Treatment: Which Is the Key Target?

Abstract

Recent clinical trials have shown several multi-target tyrosine kinase inhibitors (TKIs) to be effective in the treatment of osteosarcoma. However, these TKIs have a number of targets, and it is yet unclear which of these targets has a key role in osteosarcoma treatment. In this review, we first summarize the TKIs that were studied in clinical trials registered on ClinicalTrials.gov. Further, we compare and discuss the targets of these TKIs. We found that TKIs with promising therapeutic effect for osteosarcoma include apatinib, cabozantinib, lenvatinib, regorafenib, and sorafenib. The key targets for osteosarcoma treatment may include VEGFRs and RET. The receptor tyrosine kinases (RTKs) MET, IGF-1R, AXL, PDGFRs, KIT, and FGFRs might be relevant but unimportant targets for osteosarcoma treatment. Inhibition of one type of RTK for the treatment of osteosarcoma is not effective. It is necessary to inhibit several relevant RTKs simultaneously to achieve a breakthrough in osteosarcoma treatment. This review provides comprehensive information on TKI targets relevant in osteosarcoma treatment, and it will be useful for further research in this field.

Keywords: RET; RTKs; TKIs; VEGFRs; osteosarcoma; target therapy.

Figure 1

The general structural characteristics and activation mechanism of an RTK. RTKs are transmembrane glycoproteins that consist of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular kinase domain. They are activated by ligand binding and then transduce the extracellular signal to the cytoplasm by phosphorylating tyrosine residues on the receptors themselves (autophosphorylation) and on downstream signaling proteins.

Figure 2

The chemical structure of protein tyrosine kinases.

Figure 3

A visual interaction map of the different targets of the different drugs. Preclinical data indicate that all eight targets shown in the figure play an important role in the progression of osteosarcoma. However, clinical trials in osteosarcoma have demonstrated the low efficacy of single-target therapy by inhibiting VEGFs (by bevacizumab), KIT and PDGFRs (by imatinib), and IGF-1R (by cixutumumab). The results of these clinical trials suggest that the inhibition of one type of targets in the treatment of osteosarcoma is not feasible. PFS, progression-free survival; TKI, tyrosine kinase inhibitor; PR, partial response; VEGFR, vascular endothelial growth factor receptor; KIT, stem cell factor receptor; RET, rearranged during transfection; FGFR1, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; SD, stable disease.