49P Targeting IGF1R in Osteosarcoma

The insulin-like growth factor pathway plays a critical role in the development and progression of many pediatric malignancies, including osteosarcoma (OS). Once the IGF-pathway is activated through its ligands, it promotes cell survival and mitogenesis. Upregulation of IGF1R is concomitant with disease progression, treatment resistance and a poor prognosis. Therefore, IGF1R serves as an attractive target for anticancer therapy. Unfortunately, the IGF1R-targeted therapies tested in clinical studies were not very efficient and patients developed therapeutic resistance. Previous investigations suggested that Src, a protein tyrosine kinase, can directly phosphorylate IGF1R and mediates therapeutic resistance against IGF1R inhibitors, but the concerning mechanisms still remain to be elucidated. The effects of ceritinib (an off-label inhibitor of IGF1R) and dasatinib (a Src inhibitor) on the proliferation of HOS- and patient-derived OS primary cells were detected via WST-1 proliferation assay. To observe the inhibitory mechanisms of the drug effects on protein level, western blots were performed. The proliferation of HOS cells was only inhibited when treating the cells with ceritinib and dasatinib in combination. On protein level the drugs showed inhibitory effects on their targets IGF1R and Src in combination and in single-agent treatment. The proliferation of patient-derived primary cells was efficiently decreased by treatment with ceritinib and dasatinib in combination and partially by treating the cells with ceritinib or dasatinib alone. Intriguingly, there was no detectable effect of ceritinib alone on IGF1R phosphorylation while, dasatinib, as well as the combination of ceritinib and dasatinib, inhibited the phosphorylation of IGF1R and Src. Inhibitory effects of ceritinib and dasatinib are patient dependent and may be influenced by resistance mechanisms. There seems to be other receptors involved, which could explain why ceritinib alone was able to decrease the proliferation of primary cells with no measurable effects on protein level and why dasatinib was able to decrease the non-target-specific phosphorylation of IGF1R.