Ribosome biogenesis is a therapeutic vulnerability in paediatric neuroblastoma

Neuroblastoma is a heterogeneous malignant paediatric tumor with prognosis depending on patient age and disease stage. Current treatment strategies rely on four key diagnostic criteria: age, histological stage, MYCN gene status, and genomic profile. It has been reported that MYC oncogenic activity depends on ribosome biogenesis, whose hyperactivation in cancer cells supports their high proliferative capacity, and thus represent a potential therapeutic target.

we utilized the well-established IMR-32 cell line along with a panel of patient-derived neuroblastoma cell lines with varying MYCN status, which we previously established. Additionally, we generated an IMR-32 cell line expressing an shRNA targeting the ribosome biogenesis factor fibrillarin (FBL). Cell growth, apoptosis markers, and cell cycle regulators were analyzed. Expression of ribosome biogenesis factors was assessed using publicly available datasets and RT-qPCR data from an in-house neuroblastoma cohort.

We explored whether ribosome biogenesis represents a vulnerability in neuroblastoma. Our findings demonstrate that inhibition of RNA polymerase I using CX-5461 and BMH-21 suppressed cell proliferation at nanomolar concentrations and induced ribosomal stress, leading to activation of apoptosis and the p21 pathway. Furthermore, we identified FBL as a marker of poor prognosis in neuroblastoma. Consistently, FBL knockdown reduced neuroblastoma cell proliferation, supporting its potential as a therapeutic target.

Our study reinforces the therapeutic potential of ribosome biogenesis inhibition in neuroblastoma and expands the list of potential targets to include rRNA maturation factors. These findings highlight the promise of targeting ribosome biogenesis as a novel approach for neuroblastoma treatment.