Target Actionability Review: a systematic evaluation of replication stress as a therapeutic target for paediatric solid malignancies

Keller, KM; Krausert, Sonja; Gopisetty, Apurva; Luedtke, Daniel A; Koster, Jan; Schubert, Nil A.; Rodríguez, Ana Isabel Enríquez; Hooff, Sander R. van; Stichel, Damian; Dolman, M. Emmy M.; Vassal, Gilles; Pfister, Stefan M.; Caron, Hubert; Stancato, Louis F.; Molenaar, Jan J.; Jäger, Natalie; Kool, Marcel

doi:10.1016/j.ejca.2021.11.030

Cited by 16 publications

(10 citation statements)

References 31 publications

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“…1). Altogether, our findings were consistent with the GDSC2 dataset and other published literature which demonstrates differential sensitivity to PARP inhibitors between and within pediatric tumor types [20].…”

Section: Parp As a Drug Target In Pediatric Solid Malignanciessupporting

confidence: 92%

“…Our study is not the first to identify PARP as a potential target in pediatric solid malignancies. In fact, in our recent systematic review of replication stress as a therapeutic target for pediatric cancers, PARP presented as the most robustly investigated target within these pathways [ 20 ]. However, despite an abundance of data, PARP has not been thoroughly considered in the broader context of pediatric cancer.…”

Section: Discussionmentioning

confidence: 99%

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The potential of PARP as a therapeutic target across pediatric solid malignancies

et al. 2023

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Background Pediatric cancer is the leading cause of disease-related death in children and the need for better therapeutic options remains urgent. Due to the limited number of patients, target and drug development for pediatrics is often supplemented by data from studies focused on adult cancers. Recent evidence shows that pediatric cancers possess different vulnerabilities that should be explored independently from adult cancers. Methods Using the publicly available Genomics of Drug Sensitivity in Cancer database, we explore therapeutic targets and biomarkers specific to the pediatric solid malignancies Ewing sarcoma, medulloblastoma, neuroblastoma, osteosarcoma, and rhabdomyosarcoma. Results are validated using cell viability assays and high-throughput drug screens are used to identify synergistic combinations. Results Using published drug screening data, PARP is identified as a drug target of interest across multiple different pediatric malignancies. We validate these findings, and we show that efficacy can be improved when combined with conventional chemotherapeutics, namely topoisomerase inhibitors. Additionally, using gene set enrichment analysis, we identify ribosome biogenesis as a potential biomarker for PARP inhibition in pediatric cancer cell lines. Conclusion Collectively, our results provide evidence to support the further development of PARP inhibition and the combination with TOP1 inhibition as a therapeutic approach in solid pediatric malignancies. Additionally, we propose ribosome biogenesis as a component to PARP inhibitor sensitivity that should be further investigated to help maximize the potential utility of PARP inhibition and combinations across pediatric solid malignancies.

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Section: Parp As a Drug Target In Pediatric Solid Malignanciessupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

The potential of PARP as a therapeutic target across pediatric solid malignancies

et al. 2023

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“…These results are highly important for understanding early events leading to cancer development, as different mechanisms may underlie the oncogene-induced replication perturbation driving genomic instability. They reveal the complex nature of oncogene-induced replication stress, which should be taken into consideration when replication inhibitors are considered as a therapeutic tool for cancer ( Keller et al., 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Topoisomerase 1-dependent R-loop deficiency drives accelerated replication and genomic instability

et al. 2022

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“…Altogether our study demonstrates the potential of using chromosomal aberrations to guide preclinical development of targeted therapeutic approaches and adds to the mounting evidence that CHK1 might be an effective therapeutic target for the treatment of NB (13).…”

Section: Introductionmentioning

confidence: 53%

“…Further investigation revealed MYCN amplification (MNA) as a potential additional biomarker for CHK1 inhibition and high-throughput combination drug screens identify WEE1 kinase (WEE1) inhibition as a synergistic candidate across all 11q and MYCN phenotypes. Altogether our study demonstrates the potential of using chromosomal aberrations to guide preclinical development of targeted therapeutic approaches and adds to the mounting evidence that CHK1 might be an effective therapeutic target for the treatment of NB ( 13 ).…”

Section: Introductionmentioning

confidence: 54%

Chromosome 11q loss and MYCN amplification demonstrate synthetic lethality with checkpoint kinase 1 inhibition in neuroblastoma

et al. 2022

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Neuroblastoma is the most common extracranial solid tumor found in children and despite intense multi-modal therapeutic approaches, low overall survival rates of high-risk patients persist. Tumors with heterozygous loss of chromosome 11q and MYCN amplification are two genetically distinct subsets of neuroblastoma that are associated with poor patient outcome. Using an isogenic 11q deleted model system and high-throughput drug screening, we identify checkpoint kinase 1 (CHK1) as a potential therapeutic target for 11q deleted neuroblastoma. Further investigation reveals MYCN amplification as a possible additional biomarker for CHK1 inhibition, independent of 11q loss. Overall, our study highlights the potential power of studying chromosomal aberrations to guide preclinical development of novel drug targets and combinations. Additionally, our study builds on the growing evidence that DNA damage repair and replication stress response pathways offer therapeutic vulnerabilities for the treatment of neuroblastoma.

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Target Actionability Review: a systematic evaluation of replication stress as a therapeutic target for paediatric solid malignancies

Cited by 16 publications

References 31 publications

The potential of PARP as a therapeutic target across pediatric solid malignancies

The potential of PARP as a therapeutic target across pediatric solid malignancies

Topoisomerase 1-dependent R-loop deficiency drives accelerated replication and genomic instability

Chromosome 11q loss and MYCN amplification demonstrate synthetic lethality with checkpoint kinase 1 inhibition in neuroblastoma

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