(P 280) A CELL-BASED COMPOUND SCREENING IDENTIFIES AGENTS THAT SYNERGIZE WITH EVEROLIMUS IN SARCOMA

Objective: Everolimus, an inhibitor of the protein kinase mTOR, has shown preclinical and clinical efficacy in its ability to inhibit tumor growth. However, there has been limited success in selectively targeting mTOR alone. The aim of the current study is to find potent targets that a have synergistic effect with everolimus in sarcoma therapy.

Methods: To search for new chemical entities to enhance the efficacy of mTOR targeting by everolimus in sarcoma, a preselected drug-like small molecular compound library of kinase inhibitors was initially screened using osteosarcoma cell lines and further evaluated in chondrosarcoma and chordoma cell lines. To examine the effectiveness and underlying mechanisms behind the identified synergistic agents, several experiments were performed, including MTT and clonogenic assays as well as Western blot.

Results: The screen identified dasatinib, a Src inhibitor, as having the most potent synergism with everolimus. The results confirmed that everolimus and dasatinib have a potent synergistic effect as significant reductions in cell viability were observed as well as the mitigation of the overexpression of key signaling pathway downstream targets. Everolimus and dasatinib induce effective synergism that reduces osteosarcoma cell proliferation and elicits apoptosis. This synergistic effect is likely due to the inhibition of mTOR by everolimus which potentially facilitates dasatinib-induced Src deactivation. Dasatinib-induced Src inhibition further suppresses the activation of mTOR via the PI3K-AKT signaling pathway.

Conclusion: Our work shows targeting mTOR and the Src signaling pathways via combinatory treatment is a potentially effective therapeutic strategy for the treatment of osteosarcoma. Since everolimus and dasatinib are already in phase I/II clinical trials, this knowledge could soon be translated into the clinic.