PUBLICATION
DNA damage response deficiency enhances neuroblastoma progression and sensitivity to combination PARP and ATR inhibition
- Authors
- Hayes, M.N., Cohen-Gogo, S., Kee, L., Xiong, X., Weiss, A., Layeghifard, M., Ladumor, Y., Valencia-Sama, I., Rajaselvam, A., Kaplan, D.R., Villani, A., Shlien, A., Morgenstern, D.A., Irwin, M.S.
- ID
- ZDB-PUB-250413-5
- Date
- 2025
- Source
- Cell Reports 44: 115537115537 (Journal)
- Registered Authors
- Hayes, Madeline, Weiss, Alex
- Keywords
- ATM, BARD1, BRCA2, CP: Cancer, DNA damage, DNA damage response, PALB2, metastasis, neuroblastoma, zebrafish
- MeSH Terms
-
- Cell Line, Tumor
- Piperazines/pharmacology
- Poly(ADP-ribose) Polymerases/metabolism
- Neuroblastoma*/drug therapy
- Neuroblastoma*/genetics
- Neuroblastoma*/metabolism
- Neuroblastoma*/pathology
- DNA Repair/drug effects
- Disease Progression
- Humans
- Poly(ADP-ribose) Polymerase Inhibitors*/pharmacology
- Animals
- Phthalazines/pharmacology
- Animals, Genetically Modified
- DNA Damage*/drug effects
- Zebrafish
- Ataxia Telangiectasia Mutated Proteins*/antagonists & inhibitors
- Ataxia Telangiectasia Mutated Proteins*/genetics
- Ataxia Telangiectasia Mutated Proteins*/metabolism
- PubMed
- 40220294 Full text @ Cell Rep.
Citation
Hayes, M.N., Cohen-Gogo, S., Kee, L., Xiong, X., Weiss, A., Layeghifard, M., Ladumor, Y., Valencia-Sama, I., Rajaselvam, A., Kaplan, D.R., Villani, A., Shlien, A., Morgenstern, D.A., Irwin, M.S. (2025) DNA damage response deficiency enhances neuroblastoma progression and sensitivity to combination PARP and ATR inhibition. Cell Reports. 44:115537115537.
Abstract
Sequencing of neuroblastoma (NB) tumors has revealed genetic alterations in genes involved in DNA damage response (DDR) pathways. However, roles for specific alterations of DDR genes in pediatric solid tumors remain poorly understood. To address this, mutations in the DDR pathway including Brca2, Atm, and Palb2 were incorporated into an established zebrafish MYCN transgenic model (Tg(dbh:EGFP-MYCN)). These mutations enhance NB formation and metastasis and result in upregulation of cell-cycle checkpoint and DNA damage repair signatures, revealing molecular vulnerabilities in DDR-deficient NB. DDR gene knockdown in zebrafish and human NB cells increases sensitivity to the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, and this effect is enhanced by inhibition of the ataxia telangiectasia and rad3-related (ATR) kinase. This work provides in vivo evidence demonstrating that alterations in certain DDR-pathway genes promote aggressive NB and supports combination PARP + ATR inhibitor therapy for NB patients with tumors harboring specific genetic alterations in DDR.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping