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Peer-reviewedCC BYnpj Precision Oncology

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

  • Adrià Molero-Valenzuela1
  • Isabel de Rojas-P1
  • Guillem Pons1
  • María José Pérez-García1
  • Gabriela Guillén1
  • Andrea Vilaplana1
  • Sergio Manresa-Vera1
  • Paula Pérez-Albert1
  • Marta Garrido2
  • Lorena Valero-Arrese1
  • Raquel Hladun1
  • Mònica Sánchez-Guixé3
6 more authors
  • Marta Miera-Maluenda1
  • Ariadna Boloix1
  • Josep Roma1
  • Aroa Soriano1
  • Lucas Moreno1
  • Miguel F. Segura1
  1. 1Childhood Cancer and Blood Disorders Group, Vall Hebron Research Institute, Instituto de Investigación Sanitaria Hospital Universitari Vall d’Hebron (IIS IR-HUVH)
  2. 2Pathology Department, Hospital Vall d’Hebron, Instituto de Investigación Sanitaria Hospital Universitari Vall d’Hebron (IIS IR-HUVH)
  3. 3Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{molerovalenzuela2026loss,
  title = {{Loss of BAX in a neuroblastoma patient reveals delayed apoptosis but sustained chemotherapy sensitivity}},
  author = {Adrià Molero-Valenzuela and Isabel de Rojas-P and Guillem Pons and María José Pérez-García and Gabriela Guillén and Andrea Vilaplana and Sergio Manresa-Vera and Paula Pérez-Albert and Marta Garrido and Lorena Valero-Arrese and Raquel Hladun and Mònica Sánchez-Guixé and Marta Miera-Maluenda and Ariadna Boloix and Josep Roma and Aroa Soriano and Lucas Moreno and Miguel F. Segura},
  journal = {npj Precision Oncology},
  year = {2026},
  month = jul,
  doi = {10.1038/s41698-026-01585-w},
  url = {https://doi.org/10.1038/s41698-026-01585-w},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Loss of BAX in a neuroblastoma patient reveals delayed apoptosis but sustained chemotherapy sensitivity
AU  - Adrià Molero-Valenzuela
AU  - Isabel de Rojas-P
AU  - Guillem Pons
AU  - María José Pérez-García
AU  - Gabriela Guillén
AU  - Andrea Vilaplana
AU  - Sergio Manresa-Vera
AU  - Paula Pérez-Albert
AU  - Marta Garrido
AU  - Lorena Valero-Arrese
AU  - Raquel Hladun
AU  - Mònica Sánchez-Guixé
AU  - Marta Miera-Maluenda
AU  - Ariadna Boloix
AU  - Josep Roma
AU  - Aroa Soriano
AU  - Lucas Moreno
AU  - Miguel F. Segura
PY  - 2026
DA  - 2026/07/01
JO  - npj Precision Oncology
DO  - 10.1038/s41698-026-01585-w
UR  - https://doi.org/10.1038/s41698-026-01585-w
AB  - 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.
SN  - 2397-768X
ER  -