Abstract 3435: Targeting AKT activity inhibits MYCN and sensitizes neuroblastoma to chemotherapeutic agents

Abstract

Abstract MYCN-amplified neuroblastoma is one of the deadliest forms of childhood cancer and remains a significant clinical problem. Direct pharmacological inhibition of MYCN protein is challenging and one possible strategy to treat MYCN-amplified neuroblastoma patients is antagonizing proteins involved in its regulation. The AKT/GSK3β pathway directly regulates stabilization of MYCN, providing a therapeutic rational in MYCN-amplified neuroblastoma. In this study, we addressed the question of how AKT can play a pivotal role in MYCN-amplified neuroblastoma and whether small molecule AKT inhibitors can be promising anti-cancer compounds in children diagnosed from this cancer. Bioinformatics analysis revealed that high gene expression of AKT1 and AKT2, but not AKT3 was correlated with MYCN amplification and was significantly associated with poor outcome in neuroblastoma patients. Using RNAi-mediated depletion of AKT isoforms or pharmacological inhibition, we then demonstrated that the total AKT activity inhibition rather than the expression of particular isoforms was necessary to cause a significant decrease in neuroblastoma cell proliferation. Our results showed that AKT activity inhibition led to a significant downregulation of MYCN expression through GSK3β regulation. These results demonstrated the potential of targeting AKT activity in MYCN-amplified neuroblastoma patients. Our in vitro and in vivo data revealed promising efficacy for the pan-AKT inhibitor perifosine combined with conventional cytotoxic drugs in MYCN-amplified neuroblastoma cell. Importantly, by genetically modulating MYCN expression (siRNA or plasmid vector), our results demonstrated that MYCN expression is required for perifosine chemosensitisation. This effect was linked to the combined actions of apoptosis activation and the downregulation of ABC transporter expressions. Collectively, our data strongly support that combining the pan-AKT inhibitor perifosine, which is currently in clinical trial, with clinically-approved drugs for neuroblastoma patients could be a novel therapeutic strategy to indirectly target MYCN in neuroblastoma. Citation Format: Marion Le Grand, Kathleen Kimpton, Christine Gana, Emanuele Valli, Chelsea Mayoh, Maria Kavallaris. Targeting AKT activity inhibits MYCN and sensitizes neuroblastoma to chemotherapeutic agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3435.