BI-D1870 Induces Mitotic Dysfunction and Apoptosis in Neuroblastoma by Regulating the PI3K-Akt-mTORC1 Signal Axis

SIMPLE SUMMARY: To explore new drugs for malignant neuroblastoma, we used bioinformatics to analyze the prognostic genes, and successfully found the small molecular drug BI-D1870 based on the professional gene–drug analysis website ‘Connectivity Map’. In vivo and in vitro experiments confirmed that BI-D1870 effectively inhibited the malignant proliferation of neuroblastoma. Moreover, we found that BI-D1870 mainly inhibited the mitosis of tumor cells by regulating the PI3K-Akt-mTORC1 signal axis, thereby promoting cell apoptosis and ultimately inhibiting tumor growth. This is a drug prediction method based on a combination of massive gene map analysis and clinical survival practices, which has significant accuracy advantages over single gene changes. Furthermore, this is also the first study to explore the therapeutic benefits of BI-D1870 on NB, providing a novel clinically applicable solution for the treatment of neuroblastoma. ABSTRACT: Introduction: Neuroblastoma (NB) is one of the most common extracranial solid malignant tumors in children. The 5-year survival rate of high-risk or refractory NB is less than 50%. Therefore, developing new effective therapeutics for NB remains an urgent challenge. Materials and Methods: Based on the NB dataset TARGET-NBL in the TCGA database, the prognosis-related genes were analyzed using univariate cox regression (p < 0.01). The protein network interaction of prognostic genes was analyzed using STRING to obtain 150 hub genes with HR > 1 and 150 hub genes with HR < 1. The Connectivity Map database was used to predict a therapeutic drug: BI-D1870, a ribosomal S6 kinase inhibitor. The inhibitory effect of BI-D1870 on NB was investigated through in vivo and in vitro experiments, and its inhibitory mechanism was explored. Results: Both the in vivo and in vitro experiments showed that BI-D1870 could inhibit tumor proliferation and induce tumor apoptosis. Furthermore, we proved that BI-D1870 caused G2/M phase arrest and mitosis damage in cells. RNA-seq of cells showed that BI-D1870 may inhibit the growth of NB by inhibiting the PI3K-Akt-mTOR axis. Western blot and immunofluorescence testing showed that BI-D1870 inhibited the PI3K-Akt-mTORC1 signal pathway to regulate the phosphorylation of RPS6 and 4E BP1 proteins, inhibit protein translation, and inhibit microtubule formation, thus preventing mitotic proliferation and inducing apoptosis. Conclusions: This study provides strong support that BI-D1870 may be a potential adjuvant therapy for NB.