Targeting Functional Activity of AKT Has Efficacy against Aggressive Neuroblastoma

Abstract

MYCN-amplified neuroblastoma is one of the deadliest forms of childhood cancer and remains a significant clinical challenge. Direct pharmacological inhibition of MYCN is not currently achievable. One strategy could be to target the AKT/ GSK3β pathway, which directly regulates the stability of the MYCN protein. Numerous potent and isoform-specific smallmolecule AKT inhibitors have been developed. However, the selection of the right drug combinations in the relevant indication will have a significant impact on AKT inhibitor clinical success. To maximally exploit the potential of AKT inhibitors, a better understanding of AKT isoform functions in cancer is crucial. Here using RNAi to downregulate specific AKT isoforms, we demonstrated that loss of total AKT activity rather than isoform-specific expression was necessary to decrease MYCN expression and cause a significant decrease in neuroblastoma cell proliferation. Consistent with these observations, isoform-specific pharmacological inhibition of AKT was substantially less effective than pan-AKT inhibition in combination with cytotoxic drugs in MYCN-amplified neuroblastoma. The allosteric pan-AKT inhibitor perifosine had promising in vitro and in vivo activity in combination with conventional cytotoxic drugs in MYCN-amplified neuroblastoma cells. Our results demonstrated that perifosine drug combination was able to induce apoptosis and downregulate ABC transporter expression. Collectively, this study shows that selecting pan-AKT inhibitors rather than isoform-specific drugs to synergize with first-line chemotherapy treatment should be considered for clinical trials for aggressive neuroblastoma and, potentially, other MYCN -driven cancers.

PRMT5 activates AKT via methylation to promote tumor metastasis

“…Thus, AKT has been the focus of multiple targeting efforts, including allosteric, ATP-binding pocket and more recently PROTAC mediated inhibition strategies 51 . Indeed, pan-AKT inhibition sensitizes neuroblastoma and other cancers to chemotherapy 52 , and earlier clinical trials have tested anti-AKT therapeutics for neuroblastoma 53 . However, toxicity and resistance to AKT enzymatic activity via mutation has limited these approaches 48 , 54 .…”

Filamin A increases aggressiveness of human neuroblastoma

“… 20 Recently, it has been proposed that selecting pan-AKT inhibitors rather than isoform-specific drugs to synergize with first-line chemotherapy treatment should be considered for clinical trials for aggressive MYCN-driven NB. 21 Similarly, small molecule inhibitors effectively suppress NB tumor growth in experimental models via inhibiting ERK/MAPK signaling. 22 , 23 …”

Revolutionizing pediatric neuroblastoma treatment: unraveling new molecular targets for precision interventions

“…DPYSL3 is upregulated by GSK-3B, and their association has already been reported ( Alabed et al, 2010 ; Ong Tone et al, 2010 ). Consequently, elevated levels of MYCN, either through amplification or due to Akt-mediated GSK-3b inactivation, would suppress DPYSL3 in NB cells ( Le Grand et al, 2020 ; Gao et al, 2024 ). This mechanistic insight underscores the crucial prognostic significance of DPYSL3 expression ( Tan et al, 2013 ).…”