DNA damage response deficiency enhances neuroblastoma progression and sensitivity to combination PARP and ATR inhibition

• DOI: 10.1016/j.celrep.2025.115537
• Publication Date: 2025-04-11T17:52:25Z
• Authors: Madeline N. Hayes; Sarah Cohen-Gogo; Lynn Kee; Xueting Xiong; Alex Weiss; Mehdi Layeghifard; Yagnesh Ladumor; Ivette Valencia-Sama; Anisha Rajaselvam; David R. Kaplan; Anita Villani; Adam Shlien; Daniel A. Morgens...; Meredith S. Irwin

Sequencing of neuroblastoma (NB) tumors has revealed genetic alterations in genes involved DNA damage response (DDR) pathways. However, roles for specific DDR pediatric solid remain poorly understood. To address this, mutations the pathway including Brca2, Atm, and Palb2 were incorporated into an established zebrafish MYCN transgenic model (Tg(dbh:EGFP-MYCN)). These enhance NB formation metastasis result upregulation cell-cycle checkpoint repair signatures, revealing molecular vulnerabilities DDR-deficient NB. gene knockdown human cells increases sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, this effect is enhanced by inhibition ataxia telangiectasia rad3-related (ATR) kinase. This work provides vivo evidence demonstrating that certain DDR-pathway promote aggressive supports combination PARP + ATR therapy patients with harboring DDR.