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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月2日

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  • Adrià Molero-Valenzuela,
  • Isabel de Rojas-P,
  • Guillem Pons,
  • María José Pérez-García,
  • Gabriela Guillén,
  • Andrea Vilaplana,
  • Sergio Manresa-Vera,
  • Paula Pérez-Albert,
  • Marta Garrido,
  • Lorena Valero-Arrese,
  • Raquel Hladun,
  • Mònica Sánchez-Guixé,
  • Marta Miera-Maluenda,
  • Ariadna Boloix,
  • Josep Roma,
  • Aroa Soriano,
  • Lucas Moreno,
  • Miguel F. Segura

摘要

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.