Preclinical spheroid models identify BMX as a therapeutic target for metastatic MYCN nonamplified neuroblastoma

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Neuroblastoma (NB) is a challenging pediatric cancer, especially in high-risk patients with refractory and metastatic disease.
• Controlling tumor cell plasticity is a major hurdle in treating advanced cancers.
• Genetic and epigenetic alterations contribute to NB's aggressive nature and poor outcomes.

Purpose of the Study:

• To identify critical genes that drive the aggressiveness of neuroblastoma.
• To explore potential therapeutic targets for high-risk, MYCN nonamplified neuroblastoma.

Main Methods:

• Combined chromatin and transcriptome analyses were performed on patient-derived xenografts (PDXs), spheroids, and adherent cultures.
• Expression levels of differentially regulated genes were correlated with clinical data and tumor aggressiveness.
• The functional role of identified genes was assessed using inhibitors in preclinical models.

Main Results:

• Bone marrow kinase on chromosome X (BMX) was identified as a highly regulated gene in aggressive NB models.
• BMX expression correlated with advanced tumor stage, poor patient survival, and the mesenchymal phenotype associated with chemoresistance.
• BMX inhibition reversed the aggressive cellular state, enhanced chemosensitivity, and reduced tumor growth in preclinical models.

Conclusions:

• Bone marrow kinase on chromosome X (BMX) is a critical driver of neuroblastoma aggressiveness and chemoresistance.
• BMX represents a promising therapeutic target for high-risk, MYCN nonamplified neuroblastoma.
• Targeting BMX may improve treatment outcomes for patients with refractory and metastatic neuroblastoma.