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DNA damage response deficiency enhances neuroblastoma progression and sensitivity to combination PARP and ATR
Madeline N Hayes1, Sarah Cohen-Gogo2, Lynn Kee3
1Developmental, Stem Cell and Cancer Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
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.
Insights
Genetic alterations in DNA damage response (DDR) genes promote aggressive neuroblastoma (NB) in zebrafish. Combining PARP and ATR inhibitors shows promise for treating NB patients with specific DDR gene mutations.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Neuroblastoma (NB) sequencing reveals genetic alterations in DNA damage response (DDR) pathways.
- The specific roles of DDR gene alterations in pediatric solid tumors are not well understood.
Purpose of the Study:
- To investigate the impact of DDR gene mutations on NB development and identify therapeutic vulnerabilities.
- To evaluate the efficacy of PARP and ATR inhibitors in DDR-deficient NB models.
Main Methods:
- Incorporation of Brca2, Atm, and Palb2 mutations into a zebrafish MYCN transgenic model.
- Gene knockdown studies in zebrafish and human NB cells.
- Assessment of sensitivity to olaparib (PARP inhibitor) and ATR kinase inhibition.
Main Results:
- DDR gene mutations enhanced NB formation and metastasis in zebrafish.
- Upregulation of cell-cycle checkpoint and DNA repair signatures observed in DDR-deficient NB.
- DDR gene knockdown increased NB cell sensitivity to olaparib, potentiated by ATR inhibition.
Conclusions:
- Alterations in specific DDR genes promote aggressive NB.
- Combination PARP + ATR inhibitor therapy is a potential treatment strategy for NB patients with DDR alterations.
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