High-risk
neuroblastoma (NB) represents a major clinical challenge in pediatric oncology due to relapse of metastatic, drug-resistant disease, and treatment-related toxicities. An analysis of 1235 primary NB patient dataset revealed significant increase in AKT1 and AKT2 gene expression with
cancer stage progression. Additionally, Both AKT1 and AKT2 expression inversely correlate with poor overall survival of NB patients. AKT1 and AKT2 genes code for AKT that drive a major oncogenic cell signaling pathway known in many
cancers, including NB. To inhibit AKT pathway, we repurposed an
antiviral inhibitor
BX-795 that inhibits PDK1, an upstream activator of AKT.
BX-795 potently inhibits NB cell proliferation and colony growth in a dose-dependent manner.
BX-795 significantly enhances apoptosis and blocks cell cycle progression at mitosis phase in NB. Additionally,
BX-795 potently inhibits
tumor formation and growth in a NB spheroid
tumor model. We further tested dual therapeutic approaches by combining
BX-795 with either
doxorubicin or
crizotinib and found synergistic and significant inhibition of NB growth, in contrast to either drug alone. Overall, our data demonstrate that
BX-795 inhibits AKT pathway to inhibit NB growth, and combining
BX-795 with current
therapies is an effective and clinically tractable therapeutic approach for NB.