Targeting MYC in Ewing sarcoma

Poor survival and limited treatment options for patients with relapsed/metastatic Ewing sarcoma (ES) highlights the need for better targeted therapeutic approaches. The upregulation of MYC-C by the EWSR1-ETS fusion is an attractive therapeutic target in ES. Due to their intrinsically disordered nature, designing small molecules to directly target the MYC proteins has been challenging. The stabilisation of the MYC proteins by the Aurora kinases presents an actionable target to induce MYC degradation and cell death. Aurora kinase A (Aurora A) stabilises MYC-N in neuroblastoma and MYC-C in hepatocellular carcinoma. I hypothesised that Aurora A regulates MYC-C in ES, and the Aurora kinase inhibitors might be used to reduce MYC-C driven tumorigenesis. Confirming my hypothesis I have successfully identified an interaction between MYC-C and Aurora A in ES cell lines and patient derived cultures using proximity ligation assays. Characterisation of ES cells confirmed heterogeneous expression of Aurora A, Aurora kinase B (Aurora B) and MYC-C. Immunohistochemistry revealed the cytoplasmic localisation of MYC-C and Aurora A protein in tumours from ES patients. Survival analysis of RNA data suggests that high expression of Aurora A and Aurora B in tumours at diagnosis predicts poor survival for patients with ES, highlighting their potential use as prognostic biomarkers. From a panel of Aurora kinase inhibitors and PROTACs I identified AMG900 as the most effective inhibitor at low nanomolar concentrations. AMG900 significantly decreased cell viability and induced apoptosis. The levels of MYC-C and Aurora A protein were decreased following treatment with AMG900. In summary, I have shown that MYC-C and Aurora A interact in ES cells, and that Aurora kinase inhibitors decrease levels of MYC-C protein leading to a reduction in viable cell number. Aurora kinase inhibitors are candidate therapeutics for the treatment of ES and could be beneficial for patients. This requires further investigation.