Potential use of MYCN and AURKA dual inhibitors for the treatment of pediatric cancers

Aberrant activation of MYCN through genomic copy gain is a defining feature of high-risk neuroblastoma, which continues to have poor clinical outcomes despite intensive therapy. In MYCN-amplified tumors, AURKA contributes to malignant progression by stabilizing MYCN via a protein-protein interaction. Transcriptomic analysis of the St. Jude Children's Research Hospital database revealed that neuroblastomas co-overexpressing high levels of MYCN and AURKA exhibit significantly worse progression outcomes compared with tumors overexpressing either gene alone. We also identified a subset of pediatric soft-tissue tumors with concurrent MYCN and AURKA overexpression, among which Ewing's sarcoma showed a strong negative correlation between co-overexpression and overall survival. Across neuroblastoma and Ewing's sarcoma cell lines, MYCN expression level positively correlated with sensitivity to dual MYCN/AURKA inhibitors, including alisertib and 6K465. To evaluate translational potential, we compared the antitumor efficacy of alisertib and DBPR728 (the prodrug of 6K465) in the SK-N-BE(2) CDX model. DBPR728 administered at 300 mg/kg once weekly produced more durable tumor suppression than alisertib at 50 mg/kg once daily for three weeks. These findings define MYCN/AURKA coactivation as a therapeutic vulnerability and support the further development of dual MYCN/AURKA-targeting agents for pediatric cancers with elevated MYCN and AURKA expression.