ArticleEBioMedicine2020
Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma.
Article in EBioMedicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 78 citations in OpenAlex.
- Trial
- Telomere maintenance mechanisms are activated in ganglioneuroblastoma and ganglioneuroma.Oncology letters · 2026Article
- Metastatic progression of pheochromocytoma and paraganglioma occurs via parallel evolution.NPJ precision oncology · 2026Article
- ATRX large deletions and truncating mutations are associated with primary induction chemotherapy resistance in high-risk neuroblastoma: a multicenter propensity-weighted cohort study.Frontiers in oncology · 2026Article
- Malignant reninoma with pulmonary metastasis and ATRX mutation treated with olaparib: a case report of specialized treatment.Frontiers in immunology · 2026Article
- Epigenetic crosstalk in neuroblastoma development and progression.Frontiers in cell and developmental biology · 2026Review
- Prpf4 sequentially regulates the expansion and maturation of erythrocyte through distinct mechanisms.Cell death discovery · 2025Article
- Review
- Silencing of SOD1 sensitises ATRX-deficient cells to camptothecin treatment through increased activity of the alternative lengthening of telomeres pathway.Human molecular genetics · 2025Article
- Phase separated condensates of ATRX regulate neural progenitor identity.Nature communications · 2025Article
- Deep graph convolutional network-based multi-omics integration for cancer driver gene identification.Briefings in bioinformatics · 2025Article
- Theranostics for Neuroblastoma: Making Molecular Radiotherapy Work Better.Journal of nuclear medicine : official publication, Society of Nuclear Medicine · 2025Article
- ATRX mutations mediate an immunogenic phenotype and macrophage infiltration in neuroblastoma.Cancer letters · 2025Article
- Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles.Nature communications · 2025Article
- Exploring high-throughput drug sensitivity testing in neuroblastoma cell lines and patient-derived tumor organoids in the era of precision medicine.European journal of cancer (Oxford, England : 1990) · 2025Article
- Alternative lengthening of telomere-based immortalization renders H3G34R-mutant diffuse hemispheric glioma hypersensitive to PARP inhibitor combination regimens.Neuro-oncology · 2025Article
- Novel variants of the ATRX gene identified in MYCN non-amplified Neuroblastoma in Brazilian patients.Clinics (Sao Paulo, Brazil) · 2025Article
- CRISPR/Cas9 technology in tumor research and drug development application progress and future prospects.Frontiers in pharmacology · 2025Review
- Defining neuroblastoma: From origin to precision medicine.Neuro-oncology · 2024Review
- The impact of targeted therapies on molecular alterations identified by an institutional molecular tumor board: an approach based on ESCAT classification.ESMO real world data and digital oncology · 2024Article
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Authors and funding
17 authors at 5 institutions in 4 countries.
Funding
Abstract
backgroundIn neuroblastoma, genetic alterations in ATRX, define a distinct poor outcome patient subgroup. Despite the need for new therapies, there is a lack of available models and a dearth of pre-clinical research.
methodsTo evaluate the impact of ATRX loss of function (LoF) in neuroblastoma, we utilized CRISPR-Cas9 gene editing to generate neuroblastoma cell lines isogenic for ATRX. We used these and other models to identify therapeutically exploitable synthetic lethal vulnerabilities associated with ATRX LoF.
findingsIn isogenic cell lines, we found that ATRX inactivation results in increased DNA damage, homologous recombination repair (HRR) defects and impaired replication fork processivity. In keeping with this, high-throughput compound screening showed selective sensitivity in ATRX mutant cells to multiple PARP inhibitors and the ATM inhibitor KU60019. ATRX mutant cells also showed selective sensitivity to the DNA damaging agents, sapacitabine and irinotecan. HRR deficiency was also seen in the ATRX deleted CHLA-90 cell line, and significant sensitivity demonstrated to olaparib/irinotecan combination therapy in all ATRX LoF models. In-vivo sensitivity to olaparib/irinotecan was seen in ATRX mutant but not wild-type xenografts. Finally, sustained responses to olaparib/irinotecan therapy were seen in an ATRX deleted neuroblastoma patient derived xenograft.
interpretationATRX LoF results in specific DNA damage repair defects that can be therapeutically exploited. In ATRX LoF models, preclinical sensitivity is demonstrated to olaparib and irinotecan, a combination that can be rapidly translated into the clinic.
fundingThis work was supported by Christopher's Smile, Neuroblastoma UK, Cancer Research UK, and the Royal Marsden Hospital NIHR BRC.
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