Loss of BAX in a neuroblastoma patient reveals delayed apoptosis but sustained chemotherapy sensitivity.

The clinical interpretation of rare genomic alterations remains a major challenge in precision oncology, particularly in pediatric cancers. We describe a relapsed high-risk neuroblastoma harboring biallelic BAX inactivation, caused by a pathogenic mutation in one allele (p.E41Gfs*33) and loss of the second, resulting in complete tumor BAX deficiency. To clarify the functional and therapeutic implications of this alteration, BAX-deficient neuroblastoma models were generated and systematically analyzed. Despite complete BAX loss, tumor cells remained sensitive to conventional chemotherapy and to the BCL-2 inhibitor venetoclax, displaying delayed yet preserved cell growth arrest and apoptotic activation. Mechanistic analyses revealed partial compensatory BAK-mediated apoptosis, while combined BAX/BAK depletion suppressed caspase activity and uncovered features consistent with caspase-independent cell death. Together, these findings demonstrate that BAX loss alone does not confer chemoresistance and underscore the importance of functional validation to refine genomic-driven treatment decisions in precision pediatric oncology.